Podcasts about vegfr

El Dr. Javier Martín Broto, oncólogo médico del Hospital Universitario Fundación Jiménez Díaz en Madrid, España, presenta un resumen de los estudios que considera más relevantes en el ámbito de sarcomas expuestos durante el Congreso de ESMO 2024. EREMIS: estudio fase II que evaluó el uso de regorafenib como terapia de mantenimiento en sarcomas de partes blandas. Este diseño incluyó pacientes que recibieron previamente seis ciclos de quimioterapia basada en doxorrubicina y lograron al menos una estabilización o una respuesta objetiva. GEIS-52: estudio fase II, el cual es parte de una investigación impulsada por el grupo español de investigación en sarcomas que explora la combinación de sunitinib y nivolumab en pacientes con sarcoma de tejidos blandos. C-800-01: estudio fase I que evaluó botensilimab más balstilimab en una de las cohortes de angiosarcomas y sarcomas. Multisarc: estudio fase II/III, aleatorizado de medicina de precisión en sarcomas avanzados de tejidos blandos para la identificación de alteraciones genéticas accionables. Estudio que evalúa lenvatinib frente a placebo en pacientes con tumores del estroma gastrointestinal en progresión, específicamente en aquellos que han progresado después de recibir al menos tratamientos previos con imatinib y sunitinib. Estudio que analiza olverembatinib en tumores del estroma gastrointestinal de tipo wall type con deficiencia de SDH. En este estudio olverembatinib muestra una actividad superior a la observada con regorafenib y sunitinib en términos de supervivencia libre de progresión. AXAGIST: estudio fase II que evalúa la combinación de avelumab (un inhibidor de PD-L1) y axitinib (un inhibidor de VEGFR) en pacientes con tumores del estroma gastrointestinal avanzados o metastásicos que han progresado después de terapias estándar. 1721MO: estudio que evalua la seguridad y eficacia de olutasidenib, un inhibidor de la mutación IDH1, para el tratamiento del condrosarcoma con mutación IDH1 recurrente/recidivante o localmente avanzado o metastásico. MOTION: estudio fase III, aleatorizado, controlado con placebo y doble ciego de vimseltinib (DCC-3014) para el tratamiento del tumor de células gigantes tenosinoviales.     Fecha de grabación: 10 de octubre de 2024.                            Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

In this episode of JCO Article Insights, Rohit Singh interviews Dr. Ticiana Leal on the editorial, "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade." TRANSCRIPT The guests' disclosures can be found in the transcript. Dr. Rohit Singh: Hello and welcome to JCO's Article Insights. I am your host Rohit Singh and today we will be discussing the JCO article, “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade.” And we are joined by the senior author of the article, Dr. Ticiana Leal. Dr. Leal is an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and she serves as director of Thoracic Medical Thoracic Oncology Medical Program and Multidisciplinary Thoracic Oncology Leader at the Winship Cancer Institute. She also served as a member of the Board of Directors at the Georgia Society of Clinical Oncology.  Dr. Leal, welcome to our podcast and thank you for joining us. Dr. Ticiana Leal: Thank you, Rohit. Thank you for this interesting opportunity to discuss our editorial. My co-authors and I are very glad to be here today. So, Dr. Jennifer Carlisle and Dr. Liu were co-authors with me on this editorial. Dr. Rohit Singh: It's a really good article. And just for our audiences, the article again, titled “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade,” it discusses the challenges and the potential strategies for overcoming resistance to immune checkbox inhibitors in patients with non-small cell lung cancer. In this article, Dr. Leal and colleagues talk about the second line of drug when the patient developed disease progression while immunotherapy and they develop resistance and their definitions and what to do.  So, to Dr. Leal, can you please explain the mechanisms of primary and acquired resistance to immune check prohibitors in non-small cell lung cancer? I also saw in your article you proposed the definition of immunotherapy resistance in solid tumors, distinguishing between primary resistance and acquired resistance. So, if you can please share your thoughts and explain their mechanism. Dr. Ticiana Leal: So primary resistance and acquired resistance are related to tumor intrinsic and tumor extrinsic factors. And this is mainly clinically defined as of now according to previous response patterns and timing of occurrence, and these definitions can be heterogeneous, and we certainly think that biologically they can be very different. And it can be different according to prior therapy, whether patients got immunotherapy as PD-1, PD-L1 inhibitor alone or combination strategy with CTLA-4, or the combination with chemotherapy. But the patterns of resistance can be very different and can be based on defects and antigen presentation. It can also be due to tumor microenvironment immunosuppressive effects, and there are also additional inhibitory checkpoints that can be involved.  The definition in terms of when to call it primary or acquired resistance at this point has really been based on consensus guidelines by SITC, by Esmo, as well as our group Lung-MAP has developed clinical trials in this space. Specifically, through Lung-MAP, we've defined and incorporated the definition of acquired resistance as patients who have had prior exposure of 84 days or greater and then have had progression of their disease.  Dr. Rohit Singh: I can see why it is so challenging to come up with a standard definition for immune checkpoint resistance and I think incorporating these definitions and predictive biomarkers for clinical trial design is going to be more important going forward. Your article talks about CONTACT-01 study, so can you please discuss the CONTACT-01 study and how the shifting treatment paradigm in the first-time study impacted it and at the same time also discuss the potential implication of the differential outcome observed between the men and women in the CONTACT-01 study. Dr. Ticiana Leal: CONTACT-01 was a much-awaited study. The authors, Dr. Neal et al, looked at a very important question in the area of immunotherapy resistance. So, CONTACT-01 was a randomized phase three global study that investigated the combination of cabozantinib plus atezolizumab versus docetaxel in patients previously treated with chemotherapy and immunotherapy. And as background, cabozantinib is an inhibitor of multiple receptor tyrosine kinases including VEGFR-2, MET, RET and TAM family kinases. Preclinically, cabozantinib could lead to immuno permissive tumor microenvironment and so it was rational to combine it with a PD-1 inhibitor. In early results of a phase 1B expanded cohort of COSMIC-021 showed really promising results of this combination which led to the rationale of CONTACT-01. In this study, however, patients that were included had different prior treatment sequences. They could have had prior immunotherapy alone followed by chemo or the opposite, or they could have had prior immunotherapy and then upon progression gotten a combination of immunotherapy plus chemotherapy. That to say that immunotherapy rechallenge is something that people are doing in clinical practice given the unmet need and the desire to overcome immunotherapy resistance. But perhaps that also includes a more resistant population of patients, and these patients certainly could have had heterogeneous mechanisms of resistance which could have impacted these results.   The study did not meet the primary endpoint of overall survival. We saw a median overall survival of 10.7 months with the combination of atezo plus cabo and 10.5 months with docetaxel alone. In terms of the differences between sex that we saw in the CONTACT-01 study, just to go back in terms of the preclinical studies that have been done, there have been some preclinical studies that demonstrated that perhaps there may be some biological differences in models of different genders in mice. However, in the clinical setting, there have been, I think, contradicting results. A meta-analysis showed that perhaps women derive less benefit than men. Other studies have shown that perhaps women have more adverse events to immunotherapy. In this study specifically, only about 20% of the patients enrolled were women and the majority actually had non squamous histology. And we saw here less benefit for immunotherapy in women. But again, I think the numbers here are quite small. This is an exploratory analysis and I do think it highlights though the importance of making sure that we include populations and have higher rates of accrual, not only in women, but in other representative populations. In this study, only about 1% of the patients were black. Dr. Rohit Singh: Yeah. Thank you so much for highlighting those disparities. I think it's very important to make sure that we have proper representation of all the groups in our trials. I think based on just coming off the VEGF inhibitors, I think the Lung-MAP trial S1800A, showed a significant improvement in median OS with the combination of pembrolizumab and ramucirumab compared to standard of care. Do you envision any future commission therapies targeting the VEGF pathway with immune prohibitors in non-small cell lung cancer?  Dr. Ticiana Leal: I definitely think that targeting VEGF with multikinase TKIs based on the studies that we have seen, several now randomized phase 3 studies showing that this strategy is ineffective. So, this has been quite disappointing. But we've now seen the results of CONTACT-01, that we're just discussing here, but also other studies, including SAPPHIRE, which was also a randomized phase 3 that investigated nivolumab plus another VEGF multikinase TKI, sitravatinib. And then we also saw LEAP-008, which was a negative study investigating lenvatinib plus pembrolizumab. There still is a question though, whether you can target the VEGF pathway inhibition with a monoclonal antibody, so that's ramucirumab targeting VEGFR-2 plus ICI, and whether that can actually be an effective strategy. In our Lung-MAP trial, the S1800A, this study was a randomized phase 2. Here we used the definition of acquired resistance of patients receiving prior immune checkpoint inhibitor for a minimum of 84 days, and they were randomized to the combination of pembrolizumab plus ramucirumab versus investigator's choice of standard of care, which did include docetaxel, ramucirumab, docetaxel gemcitabine and methotrexate. This was a positive study. It led to significant improvement in median overall survival and there weren't any significant safety signals here. And we're waiting for another confirmatory study called the Pragmatica-Lung study.  Dr. Rohit Singh: Yeah, I did have one patient who raced through pembro, and I utilized this combination and was able to get some responses.  You mentioned Pragmatica-Lung trial. Can you provide more information about the ongoing Pragmatica-Lung trial and its potential impact on the treatment paradigm? Dr. Ticiana Leal: Yeah, the Pragmatica-Lung trial is an ongoing study, S2302. This is an effort that is ongoing. Dr. Karen Reckamp is the chair of this study. And this is a study that actually has a very, I think, modern study design. The term Pragmatica, this is an effort that is supported by the NCI to really propose a clinical trial design that is pragmatic to promote diversity and inclusion in clinical trials. The aim of this trial specifically is to validate what we saw in terms of overall survival in S1800A. So, in this study, patients with previously treated advanced non-small cell lung cancer are randomized 1:1 to the combination of pembrolizumab plus ramucirumab versus standard of care for patients previously treated with immunotherapy and chemotherapy for stage 4 recurrent non-small cell lung cancer. Primary endpoint here is overall survival. And I think this kind of highlights what we were talking about in terms of empowering investigators to treat patients in a clinical trial more so like a real-world setting. And I think this can be paradigm changing and decrease barriers to enrollment and also include now the real-world population that we see in clinical practice. Dr. Rohit Singh: Yeah, changing gears a little bit. I think your article also mentioned other agents that have been tested in ICI resistance settings, like lenvatinib-sitra. However, those trials results have been disappointing. What are the possible reasons behind those dose point results with multikinase inhibitors?  Dr. Ticiana Leal: We saw some really interesting, promising overall survival results with these combinations in phase two setting. In the phase 1B expansion with CONTACT-01, we saw prolonged overall survival that we thought would be promising enough to investigate in a phase 3. Ultimately, I don't know because there weren't any biomarkers that we could really tease out what was going on. Again, to highlight that both in LEAP-008 as well as CONTACT-01, there was no definition of immunotherapy resistance, which could have impacted, and we did choose the definition for SAPPHIRE, that patients had to have acquired resistance and immunotherapy had to be the most recent prior therapy. Ultimately, one potential reason for why these are not effective could be that this targeting with a multikinase TKI with multiple targets is ineffective, and you really have to target VEGF more precisely, which is the case here of ramucirumab, which targets VEGFR-2, and whether there are differences between a TKI and a monoclonal antibody may also impact the outcomes here.  Dr. Rohit Singh: You mentioned biomarkers. Do you think, are there any other potential biomarkers beyond PDL-1 or human mutation burden expression that can help us predict the response image checkpoint, especially in non-small cell lung cancer? Dr. Ticiana Leal: I think that's a great question. I definitely think that more effort needs to be dedicated, and of course, there are multiple efforts in this direction. One of the challenges, obviously, has been to obtain tissue to do this biomarker testing in clinical trials. When you look at CONTACT-01, they did PDL-1 expression, but this was all based on archival tissue and it was all based on standard of care, local testing. So, a lot of heterogeneity there, and certainly using PDL-1 at baseline from initial diagnosis for a second line trial may have significant flaws there. Ultimately, right now, for clinical practice, there isn't anything that's ready for prime time. But certainly, it sounds like, based on what we're seeing, that combining biomarkers is more likely to improve the accuracy. And I think a single biomarker alone is probably going to have insufficient predictive capacity. It'd be great to be able to better comprehensively characterize an individual's tumor, to individualize immunotherapy strategies in this relapse setting.  Dr. Rohit Singh: Yeah, definitely. We need more, better biomarkers. Coming to your point of heterogeneity, PD-L1. I myself had a patient, when we got PDL expressions from one site, they gave us one to 49%. However, for the testing, I sent the patient to a further lab at outset and PDL turned out to be 80%. But that was from a different site because of the bio sets only. Yeah, to your point, it's very heterogeneous and definitely we need to be more cautious interpreting those.  In that trial, in CONTACT-01, we have, through the patient who have oncogenetic lung cancer. Are there any plans to explore the role of immune checkpoint in oncogenetic lung cancer, especially like non-EGFR, non ALK? I know those are the ones that we have seen in multiple studies that don't respond but are other oncogenetic lung cancer is getting more and more target treatments coming out for non-small lung cancer? Dr. Ticiana Leal: Yeah. So, for patients with driver mutations, the paradigm has been well established that if there is a driver mutation, the patient should receive the appropriate targeted therapy. Immunotherapy as monotherapy has been ineffective in a lot of the patients with driver mutations beyond EGFR and ALK, certainly RET and HER2, ROS1, or other driver mutations that we believe that immunotherapy alone is ineffective. However, we are seeing some interesting ongoing clinical trials, or completed clinical trials investigating immunotherapy in patients with driver mutations. Going back to the EGFR population, we recently saw the results of HARMONi-A, which investigated ivonescimab, which is a bispecific antibody hitting PD-1, and VEGF, that in combination with chemotherapy, improved progression free survival in patients with EGFR mutated, non-squamous, non-small cell lung cancer with progression on prior TKI treatment. So, I think it is still an area of active investigation, and I do think that ongoing trials, perhaps with different PD-1, PD-L1 combination strategies such as bispecifics may be interesting but does require investigation. Dr. Rohit Singh: Yeah, definitely. It looks like combination therapy is going to be the most likely answer coming forward with more research, we're able to figure out the best possible treatment in this subgroup of patients. Considering the current challenges and ongoing research efforts, how do you see the field of non-small cell treatment evolving in coming years? Dr. Ticiana Leal: This is an interesting and important question. I think it's been really exciting to be working in thoracic oncology research. We have seen that these research efforts have led to advancement in the field. I think we need to continue to partner and collaborate with institutions, partner with industry, and also with patients and patient advocates to design clinical trials that are really going to focus on the needs of our patients in clinical trials. The gap in the second line and beyond after immunotherapy failure is a significant one. So, I do think that the challenges are to continue to develop biomarkers, to really understand who will benefit from immunotherapy strategies, who benefits from combinations, and most importantly, who does nothing. I think biomarkers are going to be something that we need to continue to incorporate in clinical trials, and I do think that there's a lot of room for hope and promise in the field. We've seen some interesting results with antibody drug conjugates and the combinations there may also be of interest. And then other important strategies, we're looking at T Cell engagers and different drugs with different mechanism of actions, including CAR T and vaccines. So beyond immune checkpoint inhibitors, I think we have different classes of drugs that may lead to different treatment strategies for patients in second line and beyond.  Dr. Rohit Singh: Yeah, certainly we have seen such extensive development in lung cancer. However, there's still a lot to be done as you just mentioned.  Thank you so much Dr. Leal for your time and great insights discussing your article with us. Dr. Ticiana Leal: Thank you. Dr. Rohit Singh: Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You'll find all ASCO shows at asco.org/podcast.    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     Dr. Leal Disclosures Consulting or Advisory Role Company name: Novocure Company name: Amgen Company name: Roche Company name: AstraZeneca Company name: Regeneron Company name: Novocure Company name: Takeda Company name: Jazz Pharmaceuticals Company name: Catalyst Pharmaceuticals Company name: Pfizer Company name: Janssen Company name: Genentech Company name: Novartis Company name: Sanofi Company name: BMS GmbH & Co. KG Company name: Abbvie Company name: OncoC4 Research Funding Company name: Pfizer Company name: Daiichi Sankyo/Astra Zeneca Travel, Accommodations, Expenses Company name: Regeneron Company name: Sanofi  

Another year, another international oncology conference in a beautiful European locale. In 2023, the world's oncology community has descended on the Spanish capital Madrid to discuss the latest and greatest scientific developments in Medical Oncology. And as always seems to be the case, Michael and Josh remain at home listening to this avalanche of information virtually. Despite a distinct lack of sun and Español, our intrepid duo will continue a grand tradition that dates back to 2022: bringing some of the best highlights from Madrid directly to your ears across a series of episodes to be released this week.In the first episode of this series, Josh and Michael start in the most difficult of tumour streams: CNS oncology, an area where outcomes continue to be incredibly poor. ESMO 2023 brought some very interesting early-phase trials and no small amount of controversy, but that silver bullet unfortunately continues to elude oncology's brightest minds. Listen on to find out more.Studies discussed in this episode. Subscription may be requiredREGOMA-OS: A large Italian multicenter, prospective, observational study analyzing regorafenib efficacy and safety in recurrent glioblastoma patients. https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/637999Glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/637931A phase I dose-expansion cohort of SYHA1813, a vascular endothelial growth factor receptor (VEGFR) 1-3 /colony-stimulating factor 1 receptor (CSF1R) inhibitor, in patients (pts) with recurrent meningioma https://esmocongress.esmo.org/esmo/esmo2023/en-GB/presentation/637997 For more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of Music Unlimited: https://pixabay.com/users/music_unlimited-27600023/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice. Hosted on Acast. See acast.com/privacy for more information.

In this episode of  the ONCOLOGY On the Go Podcast, Arvind N. Dasari, MD, and Cathy Eng, MD, speak to data supporting fruquintinib (Elunate), a VEGFR-1, -2, and -3 inhibitor as a potential treatment for patients with metastatic colorectal cancer (CRC). Dasari is an associate professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas. Eng is a David H. Johnson Chair in Surgical and Medical Oncology, a professor of medicine, co-leader of the Gastrointestinal Cancer Research Program, co-director of gastrointestinal oncology, and director of the Young Adults Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, and co-chair of the National Cancer Institute Gastrointestinal Steering Committee. These experts reviewed data from the phase 3 FRESCO-2 trial (NCT04322539), which assessed the efficacy of fruquintinib compared with placebo among patients with heavily pretreated metastatic, refractory CRC. The median overall survival (OS) in the fruquintinib and placebo arms, respectively, were 7.4 months (95% CI, 6.7-8.2) and 4.8 months (95% CI, 4.0-5.8), meeting the trial's primary end point (HR, 0.66; 95% CI, 0.55-0.80; P

BUFFALO, NY- September 20, 2023 – A new editorial paper was published in Oncotarget's Volume 14 on September 15, 2023, entitled, “Potential repurposing of DPP4 inhibitors for target therapy resistance in renal cell carcinoma.” In their new editorial, researchers Kuniko Horie and Satoshi Inoue from Saitama Medical University and Tokyo Metropolitan Institute for Geriatrics and Gerontology discuss renal cell carcinoma (RCC) — a major adult kidney cancer, which is often incidentally discovered as an asymptomatic disease on imaging in the developed countries. RCC has the most fatal disease among urological cancers, as a recent 5-year relative survival rate in the U.S. (2009–2015) is less than 80%. While RCC is known as a cancer resistant to chemo- and radio-therapies, the prognosis of RCC has been remarkably improved after the clinical application of tyrosine kinase inhibitors (TKIs) and immunotherapy. The rationale for the efficacy of TKIs in RCC is mainly based on the angiogenetic status, particularly in clear cell RCC (ccRCC) that is the most common type of RCC (70–75% of RCC), in which the loss of function mutation of Von Hippel-Lindau (VHL) tumor suppressor gene activates hypoxia inducible factor (HIF) and vascular endothelial growth factor (VEGF) pathways. The first-line TKIs that predominantly target VEGF receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) (e.g., sunitinib and sorafenib) have been clinically used since late 2000s, and the second-line TKIs such as cabozantinib, which targets more receptor tyrosine kinases including MET and TAM kinases as well as VEGFR, have been further applied to the treatment of advanced RCC since early 2010s in which the first-line TKIs are ineffective. “In our recent study, we established a panel of patient-derived ccRCC spheroid cultures with the enhancement of cancer stemness gene signature including DPP4 [9]. Focusing on TKI sunitinib sensitivity, we demonstrated that DPP4 inhibition increased sunitinib efficacy in DPP4-high RCC spheroids and DPP4 was upregulated in sunitinib-resistant RCC cells.” DOI - https://doi.org/10.18632/oncotarget.28463 Correspondence to - Satoshi Inoue - sinoue07@gmail.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28463 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, renal cell carcinoma (RCC), tyrosine kinase inhibitor (TKI), Dipeptidyl peptidase IV (DPP4), drug resistance, drug repurposing About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

A new research paper was published in Oncotarget's Volume 14 on April 10, 2023, entitled, “A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.” Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. In a new phase I trial, researchers Kristen R. Spencer, Daniella E. Portal, Joseph Aisner, Mark N. Stein, Jyoti Malhotra, Weichung Shih, Nancy Chan, Ann W. Silk, Shridar Ganesan, Susan Goodin, Murugesan Gounder, Hongxia Lin, Jiadong Li, Robert Cerchio, Christina Marinaro, Suzie Chen, and Janice M. Mehnert from Rutgers University, Dana-Farber Cancer Institute, and the Perlmutter Cancer Center of NYU Langone Health identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. “Riluzole functions as an inhibitor of GRM1 signaling through antagonism of glutamate release, and sorafenib is a multi-kinase inhibitor targeting both the MAPK and PI3K/AKT pathways through the inhibition of RAF1, ARAF and, to a lesser extent BRAF, as well as a set of tyrosine kinases including VEGFR. Our phase I study determined the tolerable dose of this combination and investigated its biologic effects.” Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. In total, 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. “Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.” DOI: https://doi.org/10.18632/oncotarget.28403 Correspondence to: Janice M. Mehnert - Janice.Mehnert@nyulangone.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28403 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - GRM1, riluzole, sorafenib, phase I, clinical trial About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ MEDIA@IMPACTJOURNALS.COM

This month on Episode 45 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the February 3rd and February 17th issues of Circulation Research. This episode also features an interview with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation.   Article highlights:   Pi, et al. Metabolomic Signatures in PAH   Carnevale, et al. Thrombosis TLR4-Mediated in SARS-CoV-2 Infection   Cai, et al. Macrophage ADAR1 in AAA   Koide, et al. sEVs Accelerate Vascular Calcification in CKD   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to be highlighting the articles from our February 3rd and 17th issues of Circulation Research. I'm also going to have a chat with Dr Hind Lal and Dr Tousif Sultan from the University of Alabama at Birmingham about their study, Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. But before I get to the interviews, here are a few article highlights.   Cindy St. Hilaire:        The first article I want to highlight comes from the laboratory of Dr Peter Leary at the University of Washington, and the title is Metabolomic Signatures Associated With Pulmonary Arterial Hypertension Outcomes. Pulmonary Arterial Hypertension or PAH is a rare but life-threatening disease in which progressive thickening of the walls of the lung's blood vessels causes increased blood pressure and that increased blood pressure ultimately damages the heart's right ventricle.   Interestingly, progression to heart failure varies considerably among patients, but the reasons why there is variability are not well understood. To find out, this group turned their attention to patient metabolomes, which differ significantly from those of healthy people and thus may also change with severity. Blood samples from 117 PAH patients were analyzed for more than a thousand metabolites by mass spectrometry and the patient's progress was followed for the next three years. 22 patients died within a three-year period and 27 developed significant right ventricle dilation. Other measures of severity included pulmonary vascular resistance, exercise capacity and levels of BNP, which is a metric of heart health. Two metabolic pathways, those relating to polyamine and histidine metabolism, were found to be linked with all measures of severity suggesting a key role for them in disease pathology. While determining how these pathways influence disease as a subject for further study, the current findings may nevertheless lead to new prognostic indicators to inform patient care.   Cindy St. Hilaire:        The next article I want to discuss is coming from our February 3rd issue of Circulation Research and this is coming from the laboratory of Dr Francisco Violi at the University of Rome and the title is Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection. Thrombosis can be a complication of COVID-19 and it is associated with poor outcomes, including death. However, the exact mechanism by which the virus activates platelets, which are the cells that drive thrombosis, is not clear. For one thing, platelets do not appear to express the receptor for SARS-CoV-2. They do however, express the TLR4 receptor and that's a receptor that mediates entry of other viruses as part of the immune response. And TLR4 is ramped up in COVID-19 patient platelets. This group now confirms that, indeed, SARS-CoV-2 interacts with TLR4, which in turn triggers thrombosis.   The team analyzed platelets from 25 patients and 10 healthy controls and they found that the platelet activation and thrombic activity were both boosted in the patient samples and could not be blocked using a TLR4 inhibitor. Additionally, immunoprecipitation and immunofluorescent experiments further revealed colocalization between the virus protein and the TLR4 receptor on patient platelets. The team went on to show that the signaling pathway involved reactive oxygen species producing factors p47phox and Nox2, and that inhibition of phox 47, like that of the TLR4 receptor itsel,f could prevent platelet activation. As such, this study suggests that inhibiting either of these proteins may form the basis of an antithrombotic treatment for COVID-19.   Cindy St. Hilaire:        The third article I want to highlight is coming from the lab of Shi-You Chen at University of Missouri and the title of this article is ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm. Macrophage activation plays a critical role in abdominal aortic aneurysm development, or AAA development. Inflammation is a component of this pathology; however, the mechanisms controlling macrophage activation and vascular inflammation in AAA are largely unknown. The ADAR1 enzyme catalyzes the conversion of adenosine to inosine in RNA molecules and thus this conversion can serve as a rheostat to regulate RNA structure or the gene coding sequence of proteins. Several studies have explored the role of ADAR1 in inflammation, but its precise contribution is not fully understood, so the objective of this group was to study the role of ADAR1 in macrophage activation and AAA formation.   Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development and dissection and angiotensin II infusion of ApoE knockout mice combined with a macrophage specific knockout of ADAR1 was used to study the role of ADAR1 macrophage specific contributions to AAA formation and dissection. Allograft transplantation of wild type abdominal aortas to ADAR1 haploinsufficient recipient mice significantly attenuated AAA formation. ADAR1 deficiency in hematopoietic stem cells also decreased the prevalence and the severity of AAA and it also inhibited macrophage infiltration into the aortic wall. ADAR1 deletion blocked the classic macrophage activation pathway. It diminished NF-κB signaling and it enhanced the expression of a number of anti-inflammatory microRNAs. Reconstitution of ADAR1 deficient but not wild type human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. Together these results suggest that macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism of editing the microRNAs that target NF-κB signaling, which ultimately promotes vascular inflammation in AAA.     Cindy St. Hilaire:        The last article I want to highlight is also from our February 17th issue of Circulation Research and it is coming from the lab of Shintaro Mandai at Tokyo Medical and Dental University and the title of the article is Circulating Extracellular Vesicle Propagated MicroRNA signatures as a Vascular Calcification Factor in Chronic Kidney Disease. Chronic Kidney Disease or CKD accelerates vascular calcification in part by promoting the phenotypic switching of vascular smooth muscle cells to osteoblast like cells. This study investigated the role of circulating small extracellular vesicles or SUVs from the kidneys in promoting this osteogenic switch. CKD was induced in rats and in mice by an adenine induced tubular interstitial fibrosis and serum from these animals induced calcification in in vitro cultures of A-10 embryonic rat smooth muscle cells. Intraperitoneal administration of a compound that prevents SEV biosynthesis and release inhibited thoracic aortic calcification in CKD mice under a high phosphorus diet. In Chronic Kidney Disease, the microRNA transcriptome of SUVs revealed a depletion of four microRNAs and the expression of the microRNAs inversely correlated with kidney function in CKD patients.   In vitro studies found that transected microRNA mimics prevented smooth muscle cell calcification in vitro. In silico analyses revealed that VEGF-A was a convergent target of all four microRNAs and leveraging this, the group used in vitro and in vivo models of calcification to show the inhibition of the VEGF-A, VEGFR-2 signaling pathway mitigated calcification. So in addition to identifying a new potential therapeutic target, these SUV propagated microRNAs are a potential biomarker that can be used for screening patients to determine the severity of CKD and possibly even vascular calcification.   Cindy St. Hilaire:        Today I have with me Dr Hind Lal who's an associate professor of medicine at the University of Alabama Birmingham and his post-doctoral fellow and the lead author of the study Dr Tousif Sultan. And their manuscript is titled Ponatinib Drives Cardiotoxicity by S100A8/A9-NLRP3-IL-1β Mediated Inflammation. And this article is in our February 3rd issue of Circulation Research. So thank you both so much for joining me today.   Tousif Sultan:              Thank you.   Hind Lal:                     Thank you for taking time.   Cindy St. Hilaire:        So ponatinib, it's a tyrosine kinase inhibitor and from my understanding it's the only treatment option for a specific group of patients who have chronic myelogenous leukemia and they have to harbor a specific mutation. And while this drug helps to keep these patients alive essentially, it's extremely cardiotoxic. So cardiotoxicity is somewhat of a new field. So Dr Lal, I was wondering how did you get into this line of research?    Hind Lal:                    So I was fortunate enough to be in the lab of Dr Tom Force and he was kind of father of this new area, now is very developed, it's called cardio-oncology. On those days there were basically everything started in cardio-oncology. So I just recall the first tyrosine kinase approved by FDA was in 2000 and that was... Imagine and our paper came in Nature Medicine 2005 and discovering there is... so to elaborate it a little bit, the cancer therapy broadly divided in two parts. One is called non-targeted therapy like chemotherapy, radiations, et cetera, and then there are cytotoxic drugs. So those cytotoxic drugs because they do not have any targeted name on it so they are, cardiotoxic are toxic to any organ was very obvious and understanding. When these targeted therapy came, which is mainly kinase inhibitor are monoclonal antibodies. So these are targeted to a specific pathway that is activated only in the cancer cells but not in any other cells in the body so they were proposed as like magic bullets that can take off the cancer without any cardiotoxity or minimal side effects. But even in the early phase like 2005 to 2010, these came out, these so-called targeted, they are not very targeted and they are not also the magic bullets and they have serious cardiotoxicity.   Cindy St. Hilaire:        And so what's the mechanism of action of ponatinib in the leukemia and how does that intersect with the cardiovascular system?   Hind Lal:                     Yeah, so this is very good question I must say. So what we believe at this point because, so leukemia if you know is driven by the famous Philadelphia chromosome, which is a translicational gene, one part of human chromosome nine and one part of human chromosome 22 and they translocate make a new gene which is BCR-ABL gene. And because it was discovered in Philadelphia UPENN, is named that Philadelphia chromosome, which is very established mechanism, that's how CML is driven. But what we have discovered that the cardiotoxicity driven by totally, totally different from the ponatinib is one of the inflammatory So it's kind of goodening. So this question is so good. One kind of toxicity is called on-target, when toxicity is mediated by the same mechanism, what is the mechanism of the drug to cure the cancer? So in that case your absolute is minimal because if you manipulate that, the drug's ability to cure the cancer will be affected but if the toxicity and the efficacy is driven by two different mechanism, then as in case of ponatinib seems like it's NLRP3 and inflammasome related mechanism. So this can be managed by manipulating this pathway without hampering the drug efficacy on the cancer.   Cindy St. Hilaire:        So what exactly is cardiotoxicity and how does it present itself in these patients?   Hind Lal:                     So these drugs like ponatinib, they call broader CVD effects. So it's not just cardiac, so they also in hypertensives and atherosclerosis and thrombosis, those kind of thing. But our lab is primarily focused on the heart. So that's why in this paper we have given impresses on the heart. So what we believe at this point that ponatinib lead to this proinflammatory pathway described in this paper, which is just 108A9-NLRP3-IL-1β and this inflammatory pathway lead to a cytokine storm very much like in the COVID-19 and these cytokine storms lead to excessive myocarditis and then finally cardiac dysfunction.   Cindy St. Hilaire:        Is the cytokine storm just local in the cardiac tissue or is it also systemic in the patients? Is cardiotoxicity localized only or is it a more systemic problem?   Tousif Sultan:              I would like to add in this paper we have included that we look this cytokine things and explain blood circulation, bone marrow. So the effect is everywhere, it's not local. So we didn't check other organs, maybe other organs also being affected with the ponatinib treatment.   Cindy St. Hilaire:        And what's the initial phenotype of a patient has when they start to get cardiotoxicity, what's kind of like a telltale symptom?   Hind Lal:                     So good thing that in recent years cardio-oncology developed. So initially the patient that were going for cancer treatment, they were not monitored very closely. So they only end up in cardiology clinic when they are having some cardiac events already. So thanks to the lot of development and growth in the cardio-oncology field, now most patients who going for a long-term cancer treatment, they are closely monitored by cardiology clinics.   Cindy St. Hilaire:        Got it. So they can often catch it before a symptom or an event. That's wonderful.   Hind Lal:                     Yeah, so there's a lot of development in monitoring.   Cindy St. Hilaire:        Wonderful. So you were really interested in figuring out why ponatinib induces cardiotoxicity and you mentioned that really up until now it's been very difficult to study and that's because of the limitation of available murine models. If you just inject a wild type mouse with ponatinib, nothing happens really. So what was your approach to finding relatively good murine models? How did you go about that?   Hind Lal:                     So this is the top scientific question you can ask. So like science, the field is try and try again. So initially this is the first paper with the ponatinib toxicity using the real in vivo models. Any paper before this including ours studies published, they were done on the cellular model in hiPSC, that isolated cardiomyocytes. So you directly putting the ponatinib directly the isolated cells. So this is first case when we were trying to do in vivo, maybe other attempt in vivo but at least not published. So first we also treated the animals with ponatinib and that failed, we don't see any cardiotoxic effect. And then when we going back to the literature, the clinical data is very, very clear from pharmacovigilance that ponatinib is cardiotoxic in humans. So when we're not able to see any phenotype in mouse, we realize that we are not mimicking what's happening in the humans.   So we certainly missing something. Now once again I quote this COVID-19, so many people get infected with COVID-19 but people are having preexisting conditions are on high risk to developing CVD. So there was some literature on that line. So we use this very, very same concept that if there is preexisting conditions, so likely who'd have developing future cardiac event will be more. So we use two model in this paper one atherosclerosis model which is APoE null mice mice, another is tag branding which is pressure overload model for the heart and as soon as we start using what we call comorbidity model like patient is having some preexisting conditions and we very clearly see the robust defect of ponatinib on cardiac dysfunction.   Cindy St. Hilaire:        Yeah, it's really, really well done and I really like that you use kind of two different models of this. Do you think it's also going to be operative in maybe like the diabetic mirroring models? Do you think if we expand to other comorbidities, you might also recapitulate the cardiotoxicity?   Hind Lal:                     So you got all the best questions.   Cindy St. Hilaire:        Thank you. I try.   Hind Lal:                     So because this is CML drug and lot of the risk factor for cardiovascular and cancer are common and even metabolic disease. So most of the time these patients are elderly patients and they're having metabolic conditions and most of the time they have blood pressure or something CVD risk factors. So I agree with you, it'll be very relevant to expand this to the diabetes or metabolic models, but these were the first study, we put all our focus to get this one out so news is there then we can expand the field adding additional models et cetera. But I agree with you that will be very logical next step to do.   Cindy St. Hilaire:        Yeah. And so I guess going back to what you know from the human study or the clinical trials or the human observations, are different populations of patients with CML more predisposed to cardio toxicity than others or is that not known yet?   Hind Lal:                     So one other area called pharmacovigilance. So what pharmacovigilance does patient all over the world taking these drugs. So WHO have their own vigilance system and FDA have their own, so it's called BG-Base for the WHO and it's called the FAERS for the FDA. So one can go back in those data sets and see if X patient taking this Y drug and what kind of symptoms or adverse effect they are seeing and if these symptoms are associated with something else. So there is data that if patients having CVD risk factor, they are more prone to develop ponatinib induced cardiac events. But it needs more polish like you asked the just previous question, diabetes versus maybe blood pressure means hypertension, atherosclerosis, or thrombosis. So it has not been delineated further but in a one big bucket if patients are having CVD risk factor before they are more prone and more likely to develop the cardiac events.   Cindy St. Hilaire:        So after you established that these two murine models could pretty robustly recapitulate the human phenotype, what did you do next? How did you come upon the S100A8/A9-NLRP3-IL-1β signaling circuit? How did you get to that?   Hind Lal:                     So in basic science work, whenever we do mouse is called until we get there is cardiac dysfunction, it's called phenotype, right? So mouse had a cardiac phenotype. So next step is, "Why? What is leading to that phenotype?" That's what we call mechanism. So there the best idea to fit the mechanism is using one of the unbiased approaches like you do unbiased proteomics, unbiased RNC analysis, something like this that will analyze the entire transcript like RNC and say, "Okay, these pathway are," then you can do further analysis that will indicate these pathway are different, are altered. So in this case we used RNC analysis and it came out that this yes A8 and yes A9, 100A8 and nine, they were the most upregulated in this whole set. And thereafter we were very lucky. So we started this study at Vanderbilt, where my lab was and thereafter we very lucky to move here and found Sultan who had a lot of experience with this inflammation and immune system and then Sultan may add something on this so he'll be the better person to say something on this.   Tousif Sultan:              So after our RNC analysis, so we got this S100A8 and nine as top hit with the ponatinib treatment. So then we validated this finding with our flow cytometric, qRT PCR aand then we started which pathway is going to release cytokine and all that. So we found that is NLRP3 inflammasome.   Cindy St. Hilaire:        Yeah and well and I guess maybe step back, what is S100A8/A9? What are those? Tousif Sultan:              Yeah, S10A8/A9 is a calcium binding protein. So that's also called alarmin and they basically binds with the pathogen associated pattern and other TLR2 like receptors and then start inflammatory pathway to release cytokine and all that and it's stable in heterodimer form. So S100A8 heterodimer with A9 and then bind with TLR and a start in this inflammatory pathway.   Cindy St. Hilaire:        And what type of cell is that happening in? Is that happening in the immune cells only or is it also in the cardiomyocyte, or...?   Tousif Sultan:              Yeah, we have included all this data. So from where this alarmin is coming with ponatinib treatment, so literature also suggested that neutrophils and monocytes, those cells are the potential to release the alarmin. So here we also found these two type of cells, neutrophils and monocytes. They release huge alarmin with the treatment of ponatinib.   Cindy St. Hilaire:        And so really taking this really neat mechanism to the next level, you then tried attenuating it by using broad anti-inflammatory steroid dexamethasone but also by targeting these specific components, the NLRP and the S100A specific inhibitors and they worked well. It worked really nicely. Does your data show that any of these therapies work better than the other and then are these viable options to use in humans?   Hind Lal:                     Yeah, we have some data in the paper. Are very broad which help a lot in COVID patients, far very acute infections. So in this case, situation is very different cause most of CML patients will going to take ponatinib for lifelong, there is no remission, right? So in those case, its certainly not a very attractive option. We have shown data in the paper that dexamethasone help with the heart but lead to some metabolic changes. So we have compared those with the NLRP3 inhibitors, those metabolic alterations, dexa versus the NLRP3 inhibitors, CY-09. And we demonstrated that targeting is specifically with paquinimod, our NLRP3 inhibitor CY-09, feel better. It can still rescue the cardiac phenotype without having those adverse effect on metabolic parameters.   Cindy St. Hilaire:        That's wonderful. Do you think though that because you have to take ponatinib for life, that long-term NLRP inhibition would also cause problems or...?   Hind Lal:                     So because not every patient who taking ponatinib would develop the cardiac phenotype, right? Which is like a 10%, 12%, patient developing cardiac dysfunction. So I think someone like I strongly believe paquinimod, which is inhibitor of S100A9, will be really good option or at least we have enough data that make us nail for at least a small clinical trial. And we quickly moving on that. At UAB we have our clinical cardio-oncology program and we are already in touch with the director for the clinical cardio-oncology program. So what we trying to do in that small trial is if one of the standard therapy for heart like beta blocker or ARBs inhibitor, is there any preference like one work better than the other in the standard care? So first we doing that project, then we obviously looking forward if one small clinical trial can be done with paquinimod. I strongly believe it should be helpful.   Cindy St. Hilaire:        That is wonderful. And so do you think... There's other chemotherapeutic agents or probably even other non-cancer drugs that cause cardiotoxicity, do you think this mechanism, this pathway, this S100A-NLRP-IL-1β axis is operative in all cardiotoxicities or do you think it's going to be very specific to the ponatinib?   Hind Lal:                     So it's certainly not all, but it'll be certainly more than ponatinib. So in our lab we are using another kinase inhibitor, which is osimertinib and it's not published yet, but now we know that it's also cardiotoxic because it's taking metabolic root or energetics disruption but not this pro-inflammatory part, but we're doing another project which is strep pneumonia induced cardiac dysfunction, which is called pneumonia. So strep pneumoniae, which leads to the pneumonia ,and lot patient die because of the failing heart we see here in the hospitals and we see these pathways operational over there and we gearing up to do clinical trial on that aspect as well, but it's not generalized like all kind of heart will have the same mechanism.   Cindy St. Hilaire:        It's wonderful to see you're already taking those next steps towards really kind of bringing this to a translational/clinical study. So what was the most challenging aspect of this study?   Tousif Sultan:              The challenging aspect, ponatinib is a kinase inhibitor and that was surprising for us how it's activating immune cells. Generally kinase inhibitors, inhibits all the cells like that. So that was challenging. So we repeated it many times did in vitro experiment to confirm that. So we just added, just treated in vitro immune cells with the ponatinib and confirmed it. So that was little challenging.   Cindy St. Hilaire:        So what's next? You mentioned you're going to try some clinical trials, early stage clinical trials. What's next mechanistically, what do you want to go after?   Hind Lal:                     So what we are doing next and we are very, very eagerly trying to do that. So what it was done, we used the cardiac comorbidity models, but as you know, anybody who will take ponatinib will have cancer, right? So we strongly believe that we miss one factor. There was no cancer on these. So that is very logical next step. What that will allow us to do, what rescue experiment we'll have done in this paper. So we saw, "Okay, this rescue the cardiac phenotype, which is taken care of now," but very same time, we not able to demonstrate that this is happening without hurting the cancer efficacy. So if we have the dual comorbid mouse, which have CML a real thing and we have cardiac thing, then that will allow us to demonstrate, "Okay, we got something that can take care of the cardiac problem without hurting the efficacy on the cancer." And it will be best if you also help little bit to more potentiate the cancer efficacy.   Cindy St. Hilaire:        Yes. Excellent. Well, congratulations on a beautiful study, really exciting findings. Dr Lal and Dr Sultan, thank you so much for taking the time to talk with me today.   Tousif Sultan:              Thank you so much.   Hind Lal:                     Well thank you, Cynthia. We really appreciate your time. Thank you for having us.   Cindy St. Hilaire:        Yeah, it was great.   Cindy St. Hilaire:        That's it for our highlights from the February 3rd and February 17th issues of Circulation Research. Thank you so much for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Hind Lal and Dr Tousif Sultan. This podcast is produced by Ishara Ratnayake, edited by Melissa Stoner and supported by the editorial team at Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, you're on-the-go source for most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association 2023. And the opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.  

This week, please join author Trisha Singh as she discusses her article "Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass for the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, very interesting feature discussion this week. Many times we hear in magnetic resonance imaging the use of gadolinium contrast. And remember, gadolinium is an extracellular agent. And when we apply it in the heart, we look for infarcts, or areas of the heart that are perhaps dead, or scarred over. This week's feature discusses manganese as a contrast agent and it is an intracellular contrast agent. And very interestingly, it identifies calcium handling, so it's a marker of viability. And these authors are going to apply manganese as well as gadolinium in trying to understand mechanisms behind Takotsubo cardiomyopathy. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Dr. Carolyn Lam: Oh, I'd love to tell you about the other articles. But just have to first say, I loved your description of the feature paper. It's right up your alley and I can't wait to learn more. But my first paper today I want to talk about pulse field ablation. Now, what is that? Pulse field ablation, or PFA, is a unique and novel technique to treat atrial fibrillation. It has a unique safety profile largely related to its preferentially for myocardial tissue ablation. And thus, sparing the esophagus and thus, deemed to have a unique safety profile. Now, a pentaspline catheter was the first such PFA system studied for AF ablation. And in the initial trials the catheter was used for pulmonary vein isolation and left atrial posterior wall ablation. However, following its regulatory approval in Europe, in clinical practice, physicians have ablated both these locations and expanded lesions that could be in closer proximity to the coronary arteries. Now, this is an unstudied important issue since preclinical and maybe some clinical data have raised the potential for coronary arterial spasm. Hence, the investigators led by Dr. Vivek Reddy from Icahn School of Medicine at Mount Sinai and colleagues studied the vasal spastic potential of PFA lesion sets, both remote from and adjacent to coronary arteries. Dr. Greg Hundley: Wow, Carolyn, this is a really interesting question. So what did they find? Dr. Carolyn Lam: In this retrospective analysis of a series of 25 patients undergoing PFA for atrial fibrillation in whom coronary angiography was performed pre, during and post ablation, they found that during pulmonary vein isolation and left atrial posterior wall ablation, coronary spasm did not occur. However, cavotricuspid isthmus ablation provoked severe subtotal vasospasm in five out of five consecutive patients. And this was relieved by in coronary nitroglycerin. ST elevation was not observed. No patient had severe spasm if first pretreated with parenteral nitroglycerin, either intracoronary or intravenous. And so in summary, coronary vasospasm was not provoked during PFA at locations remote from the coronary arteries. But when the energy is delivered adjacent to a coronary artery, like in cavotricuspid isthmus ablation, PFA did provoke subclinical vasospasm. And the phenomenon was attenuated by nitroglycerine administered either post hoc to treat spasm or as prophylaxis. And this is discussed in accompanying editorial, I like it, “Coronary Vasospasm in PFA Primum Non Nocere” by Drs. Estes and Sundeep and Saba. Dr. Greg Hundley: Very nice Carolyn. Very important research in this area using that particular methodology. Well Carolyn, my next study comes to us again from preclinical science. And Carolyn, this study evaluated mechanisms responsible for pulmonary hypertension. So as background, pulmonary hypertension is associated with increased expression of VEGFA and it's receptor VEGFR-2. But whether and how activation of VEGFA signal participates in the pathogenesis of pulmonary hypertension, that's unclear. And so these authors led by Dr. Yangxin Chen from Sun Yat-Sen Memorial Hospital and Sun Yat-Sen University evaluated VEGFA, VEGFR-2 signal activation and VEGFR-2 Y949 dependent vascular leak in lung samples from patients with pulmonary hypertension as well as in mice exposed to hypoxia. Dr. Carolyn Lam: Another one of those excellent translational pieces, isn't it Greg? So what did they find? Dr. Greg Hundley: Right Carolyn. So these authors found that pulmonary hypertension led to excessive pulmonary vascular leak in both patients and hypoxic mice. And this was owing to over activated VEGFA and VEGFR-2 Y949 signaling axis. Abolishing VEGFR-2 Y949 signaling via a specific point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure. This, in turn, led to alleviation of pulmonary hypertension manifestations including muscularization of distal pulmonary arterials, elevation of right ventricular systolic pressure and right ventricular hypertrophy. And so Carolyn, in summary, these results suggest that VEGFA, VEGFR-2 Y949 dependent vascular permeability is an important determinant in the pathogenesis of pulmonary hypertension and might serve as an attractive therapeutic target pathway for this disease. Dr. Carolyn Lam: Aw, thanks Greg for explaining that so well. The next paper talks about transcatheter aortic valve replacement of TAVR, recognizing that it is a well established treatment now for high and intermediate risk patients with severe symptomatic aortic stenosis. However, the question asked here is what makes some, but not all patients improve their left ventricular ejection fraction following TAVR associated after load reduction? Now, hypothesizing that circulating microRNAs may play a role here, the authors led by corresponding authors, Dr. Hosen and Jansen from University of Bonn and their colleagues profiled the differential expression of microRNAs in circulating extracellular vesicles in patients after TAVR. And in particular, the novel role of circulating microRNA 1225p in cardiomyocytes. Dr. Greg Hundley: Oh wow. So Carolyn, important study. So what did they find? Dr. Carolyn Lam: Well, first aortic stenosis increases circulating microRNA 1225p, which correlated with a lack of improvement of the EF in patients after TAVR. Extracellular vesicles harbored microRNA 1225p and facilitated its startling into the cardiomyocytes. Vesicular shuttling of this particular microRNA was regulated by a direct interaction with a multifunctional RNA binding protein called heterogeneous nuclear ribonucleoprotein U in a sequence specific manner. Extracellular vesicles containing the specific microRNA post transcriptionally repressed BCL2 an anti-apoptotic gene, which is central to cell viability and apoptosis. So in summary, Greg, an increase in extracellular vesicle microRNA 1225p in patients with aortic stenosis represents a novel mechanism for the deterioration of cardiac function in patients following TAVR. And pharmacological manipulation of this axis may improve ejection fraction and cardiac function in patients with aortic stenosis by improving the viability of cardiomyocytes, which opens the door to a potential therapeutic approach in patients with limited EF improvement following TAVR. Dr. Greg Hundley: Oh Carolyn, beautiful, beautiful description of that wonderful preclinical science. Well, let's reach into the mail bag and see what else is in the issue. And first, there's a research letter by Professor van Raalte entitled “Kidney Hemodynamic Effects of Angiotensin Receptor Blockades Sodium Glucose Co-transporter 2 Inhibition Alone and in Their Combination: A Crossover Randomized Trial in People with Type 2 Diabetes.” And Carolyn, there's also an In Depth piece from Dr. Marx entitled “GLP1 Receptor Agonist for the Reduction of Atherosclerotic Cardiovascular Risk in Patients with Type 2 Diabetes.” Dr. Carolyn Lam: Very, very nice papers, those two. There's also an exchange of letters between Drs. Hou and Sedej regarding the article, “Fine Tuning Cardiac Insulin Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.” As well as a Perspective by Dr. Eagle, “Comments on the 2022 Aortic Guidelines: Seeking More Precision in Aortic Care.” Now, let's go onto the feature discussion of all things MRI, shall we? Dr. Greg Hundley: You bet. More on manganese. Welcome listeners to this very interesting feature discussion on December 13th. And we have with us Dr. Trisha Singh from the University of Edinburgh in Edinburgh, Scotland. Welcome, Trisha. This is a fascinating study incorporating manganese cardiovascular magnetic resonance to study some of the mechanistic underpinnings of hypokinesis left ventricular hypokinesis in patients with Takotsubo syndrome. So maybe just describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Trisha Singh: Yes, of course. So we know with patients with Takotsubo syndrome, it predominantly affects middle aged women, patients present with a degree of left ventricular dysfunction, which is transient. And, unfortunately, it can be quite difficult to diagnose because it can phenotypically present very similar to an acute coronary syndrome. We know from previous studies that these patients do have ongoing symptoms despite normalization of their LV function. And actually their outcomes are not as benign as previously thought. In terms of manganese enhanced MRI imaging, we at Edinburgh University have imaged patients with other cardiac conditions such as hypertrophic cardiomyopathy, and dilated cardiomyopathy. And have established that it can be used as a surrogate marker of myocardial calcium uptake and handling. So we were very interested to see whether or not patients with acute Takotsubo syndrome have got a myocardial calcium dysfunction and more importantly whether or not this translates into long-term dysfunction and perhaps could explain their symptoms and worse prognosis in long-term. Dr. Greg Hundley: Trisha, manganese MRI. Now, we hear about gadolinium MRI, how is manganese different? You mentioned it's a nice marker for calcium handling. Is this widely used clinically? What kind of contrast does it provide? Dr. Trisha Singh: So manganese was actually one of the first contrast agents to be used with magnetic resonance imaging. It kind of came about in the 1970s and 1980s. And previous animal models have looked at how it is essentially an intracellular contrast agent. And what I mean by that is manganese is a calcium analog and therefore, in cells where they are viable and there's intact cell function, they will be taken up through a voltage gated calcium channels. So, for example, in the heart. So the theory is that manganese, when you've got normal viability, manganese is taken up into the myocardium via voltage gate calcium channels. And several studies have shown that if you then have disease myocardium, these tissues do not take up the manganese as normal tissue would. And the main difference between manganese and gadolinium is they are both paramagnetic, which is why they're helpful and useful in MRI. But gadolinium, as a compound, is too big and it cannot cross an intact cell membrane and therefore, gadolinium is more extracellular. And as, we know, accumulates in tissues where there is increased edema, or water content. So gadolinium, for all intents and purposes, is incredibly useful contrast agent, certainly what we use predominantly at the moment in clinical practice, but it is extracellular. So the theory behind manganese is that it is an intracellular contrast agent as opposed to gadolinium. And where gadolinium accumulates in disease tissue, manganese accumulates in viable tissue. So they behave almost kind of in contrast to each other. And currently, manganese is not used in clinical practice. I think the only clinical compound contrast agent utilizing manganese was mangafodipir, otherwise known as Teslascan, which I believe came off the market in 2012 and that was predominantly used for imaging liver metastasis. Dr. Greg Hundley: Well Trisha, thank you for clarifying for us the difference between manganese, the intracellular contrast agent, and gadolinium, the extracellular contrast agent, that's so widely used clinically. Well, with that description, can you describe for us now, your study population and your study design? Dr. Trisha Singh: Perfect. So the study population was we aimed to recruit 20 patients with acute Takotsubo syndrome. The diagnosis of Takotsubo syndrome was based on a clinical diagnosis, so all our patients underwent a baseline echocardiography and invasive coronary angiography. Now, for us, the coronary angiography was quite important because we wanted to ensure we ruled out anyone with an acute myocardial infarction, which can often be tricky in this cohort of patients. So after recruiting 20 patients during the acute phase of Takotsubo, they all underwent a baseline gadolinium enhanced MRI scan followed by a manganese enhanced MRI scan. And these were done at least 48 hours a part. And then about three months roughly after the acute index, they were all invited to participate in a second manganese enhanced MRI scan. Dr. Greg Hundley: Very good. So two exams separated longitudinally over time. What were your study results? Dr. Trisha Singh: Our results demonstrated that during the acute phase as one would expect, patients had a degree of left ventricular dysfunction. The majority of our patients had afibrillar Takotsubo, so had afibrillar ballooning with preservation of the basal segments. With this, we also noted that in the areas that were affected by Takotsubo, so kind of the mid ventricular wall and the apex that all patients had significantly elevated native T1 and associated T2 as well. And as we expected there was reduced uptake of manganese and therefore kind of reduced calcium uptake in the myocardium in the area affected by Takotsubo syndrome. Interesting, what we also noticed was that all these patients had significantly elevated LV mass, which has been described in previous Takotsubo papers, certainly by Professor Dawson. And when you measured the left ventricular wall thickness, the LV wall thickness is elevated in the affected and actually not even in the non-affected areas, which I suspect explains why in the acute phase people almost doubles up which kind I guess fit with kind of acute myocardial edema and intense water content. And then, three months later when these patients returned for their follow-up scan, a lot of the acute changes had resolved. So native T2 values had improved and gone back to baseline. Native T1 and post contrast T1 values had remained elevated compared to the control population. And what we found was that manganese uptake, though it had improved, it still remained abnormal and reduced compared to the control population, which is a finding that we weren't expecting to find. Dr. Greg Hundley: Very interesting. So acutely we've got extracellular water there, elevation of myocardial T2, and also impaired manganese uptake. So intracellular abnormalities with calcium handling. Then later, so three months later, we have restoration of myocardial T2 so the extra water content is absent, but we have impaired manganese uptake indicating an abnormality with calcium handling. So how do we put this all together mechanistically? What does this tell us about the pathophysiology of Takotsubo syndrome? Dr. Trisha Singh: For one thing, I think we can say that there is, as described before, there is obviously intense myocardial edema present in patients with acute Takotsubo. And I think the significant elevation in T2 and LV mass kind of all fits together. Actually interestingly, as native T2 improves in their follow-up scans, the LV mass actually all return back to normal baseline. So I think the acute edema does resolve. And as you said, interestingly, despite all of these patients, their LV function completely recover. And despite that their myocardial calcium uptake, or handling remain normal. And I think that's not been demonstrated before. And I think it just points to that there is obviously, still something going on in the myocardium and it's not behaving completely normally despite completely normal kind of gross LV function. And potentially, this might point in the direction of why these patients have ongoing symptoms. So, certainly, from our observational cohort group, about 70% of patients had ongoing symptoms and this was predominantly breathlessness and palpitations. And potentially, might be related to why patients have worse outcomes compared to the general population. Dr. Greg Hundley: Very nice. And Trisha, can you describe, was there a therapeutic intervention between the acute and then the three month later measurements? Were these patients administered any type of medical therapy and were there differences in what those therapies may have been between different patients in your study? Dr. Trisha Singh: So predominantly, most of the patient population that were started on some combination of heart treatment due to the baseline LV dysfunction. And this kind of was a combination of most of them were on Ramipril, a few of them were also on spironolactone or eplerenone. And then, every single one was on furosemide. And interestingly, I mean I appreciate, I think the population group was quite small, so it's very difficult to compare those that were on kind of full heart failure treatment versus those who were just on beta blocker and ramipril therapy. But even in that cohort there was a split of about, I think predominantly, I think 17, 16 patients were on kind just beta blockers and ramipril as opposed to beta blocker, ramipril, spironolactone. And there was no difference kind of in the recovery in manganese uptake in that cohort. But, again, the numbers are quite small, so I think it's difficult to extrapolate any kind of true meaning in that. Of course, we know there's a lack of randomized control trial data looking at how to best treat patients with acute Takotsubo syndrome and certainly, what treatment may prevent these patients from having a recurrence of Takotsubo. And I know some of the TACA registry data has looked at actually despite the fact patients of being on beta blocker, or ramipril therapy, they still go having recurrence of Takotsubo and certainly of our cohort, one of our patients went on having a recurrent episode of Takotsubo within a year of her index event and she was on aspirin, beta blocker, spironolactone as well. Dr. Greg Hundley: Very nice. And then lastly, when you made these measurements looking at the manganese uptake or lack thereof, were these in the regions of myocardium where you mentioned many had apical LV wall motion abnormalities, were they in those regions or did you also measure regions remote to where the wall motion abnormality occurred? Dr. Trisha Singh: Of course. So we took measurements in the affected regions of the heart that kind of demonstrated spironolactone syndrome. And we also took measurements in kind of, so to speak, the remote segments of the heart. Now, for the remote segments of the heart, we could only measure native T1 and post contrast T1 at 30 minutes and to measure manganese uptake well, unfortunately, what we have to do is take a measurement over time, so we'd do every two and a half minutes for 30 minutes after the manganese contrast. So we weren't able to calculate manganese uptake in the remote regions. But what we could do was measure the native T1 in the remote region, and then the post contrast T1 and see how it differed with the region of interest in the affected portion of the heart, so to speak. Dr. Greg Hundley: Very good. Well, Trisha, with this really exciting research and very nice methodology, what do you see as the next study to be performed in patients with Takotsubo? Dr. Trisha Singh: So I think, in terms of manganese enhanced imaging, I think it'd be really interesting to re-scan these patients at one year or at two years. And the question there is whether or not their manganese uptake ever recovers really. I know we previously talked about this and thought about whether or not these patients who go onto developing Takotsubo syndrome might actually have a kind of an underlying cardiomyopathy that puts them at risk of developing Takotsubo with stress. So it'd be interesting to see whether or not actually their calcium uptake ever recovers in the long-term, or whether actually they have more of a chronic heart failure type like picture. And I think another area of interest would be to see potentially using manganese imaging as a noninvasive measure of kind of myocardial calcium activity and to see whether or there's any changes with therapy over the course of months to years or so. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Trisha Singh from University of Edinburgh in Edinburgh, Scotland for bringing us this really interesting article in patients with Takotsubo syndrome demonstrating that there is a marked perturbation of myocardial manganese uptake, which is most evident in the acute phase of Takotsubo presentation, but also persists for at least three months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema. All of this suggesting that abnormal myocardial calcium handling may be implicated in the pathophysiology of Takotsubo syndrome. Well, on behalf of Carolyn and myself, we want to wish you a great week. And we will catch you next week on the run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ajjournals.org.

A new research paper was published in Oncotarget's Volume 13 on October 19, 2022, entitled, “Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer.” Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression. Previously, researchers Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Amrendra K. Ajay, Larissa Camila Ribeiro de Souza, Minghua Cao, Yueming Luo, Petra Hoegger, Carmen M. Ribas, Jurandir M. Ribas-Filho, Osvaldo Malafaia, Reinhard Lissner, Li-Li Hsiao, and Ana Maria Waaga-Gasser, from Harvard Medical School, Shenzhen Traditional Chinese Medicine Hospital, University of Wuerzburg, and Mackenzie Evangelical Faculty of Paraná, recently provided evidence for upregulation of PDGF expression in UICC stage I–IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. In their new study, the researchers sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC. “Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRβ, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors.” Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. The team then analyzed several CRC cell lines for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 protein expression. They found these receptors to be variably expressed amongst the investigated cell lines. Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor. “Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.” DOI: https://doi.org/10.18632/oncotarget.28281 Correspondence to: Ana Maria Waaga-Gasser - awaaga@bwh.harvard.edu Keywords: PDGF, VEGFR, EGFR, bypassed signaling, colorectal cancer About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter - https://twitter.com/Oncotarget Facebook - https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram - https://www.instagram.com/oncotargetjrnl/ LinkedIn - https://www.linkedin.com/company/oncotarget/ Pinterest - https://www.pinterest.com/oncotarget/ LabTube - https://www.labtube.tv/channel/MTY5OA SoundCloud - https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com. Oncotarget Journal Office 6666 East Quaker Str., Suite 1A Orchard Park, NY 14127 Phone: 1-800-922-0957 (option 2)

In this medical education podcast episode, Prof. Peter Galle and Prof. Amit Singal discuss the use of VEGFR-TKIs in the treatment of advanced or unresectable HCC and explain the immunomodulation rationale to combine it with immune checkpoint inhibitor. Combination approach has been validated recently with the atezolizumab+bevacizumab combination being the new standard of care in 1L setting for advanced HCC patients. In the context of advanced HCC, both experts share their view about the dosing approach with VEGFR-TKI and provide insight to handle the dosing when combining with PD-1 inhibitor. Both experts reiterate that biomarkers are urgently needed in HCC and summarize the current stratification of patients used to predict the response with VEGFR-TKI monotherapy or in immunotherapy combination. Finally, they emphasize that pre-habilitation of HCC patients is key to make the HCC patient fit for the best available treatment option.

Prof. Thomas Powles, a Medical Oncologist from Barts Cancer Centre in the UK and Prof. Georg Hutterer, a Urologist from the Medical University of Graz, Austria, discuss the role of VEGFR-TKIs in the treatment of advanced renal cell carcinoma (RCC) alone or in combination with immunotherapy. In this podcast, by COR2ED Medical Education, the two experts discuss key trials (CHECKMATE 214, KEYNOTE 426, CHECKMATE 9ER and CLEAR) which have led to recent updates to the ESMO and EAU treatment guidelines for RCC. Combination treatment with either VEGFR targeted therapy plus a PD-1 or CTLA-4 inhibitor in the first-line setting is discussed as well as VEGFR-TKI monotherapy options at the time of disease progression. They also focus on how to manage treatment toxicity whilst trying to optimise treatment outcomes and preserving patients’ quality of life as well as the use of biomarkers and risk stratification models.

The use of VEGFR-TKIs monotherapy in the treatment of unresectable or advanced HCC in 1L setting: Who can benefit and guidance on implementation of dosing-strategies and pre-habilitation of patients for the prediction of efficacy and toxicities in clinical practice Prof. Josep Llovet and Prof. Stephen L. Chan discuss a very interesting topic about the use of the VEGFR TKIs monotherapy in the treatment of unresectable or advanced HCC in the first-line setting. They will go into details about who can benefit from monotherapy and will share the current guidance on the implementation of the dosing strategies for the management of toxicity in the clinical practice. They discuss first line monotherapy with TKI (lenvatinib or sorafenib) for patients who are not suitable for the treatment with atezo-bev combination (around 20% of the patients) which is the current standard of care. They summarize the HCC patients who are not ideal for this I/O combination such as HCC patients with liver transplantation, high bleeding risk, impaired liver function or severe autoimmune disease. The experts discuss about which patients can benefit from TKI and provide a summary of efficacy data and safety profile from various pivotal clinical studies (including SHARP, REFLECT, IMbrave150) as well as real-world data. Dosing-strategies for VEGFR-TKIs and management of AEs are discussed as well as guideline recommendations. Finally, the experts discuss key developments over the next few years focusing on the new immunotherapy combinations approach that could become new standard of care.

El Dr. Eduardo Cárdenas Cárdenas, oncólogo médico adscrito al Centro Médico Nacional “20 de Noviembre”, ISSSTE en la Ciudad de México, México, junto con el Dr. Rubén Kowalyszyn, oncólogo médico, del Instituto Multidisciplinario de Oncología en Río Negro, Argentina, nos comentan sobre lo más destacado en tumores de cabeza y cuello, presentado en el Congreso Anual de la Sociedad Europea de Oncología Médica, resaltando los siguientes estudios: GORTEC: Estudio fase III, aleatorizado de avelumab + cetuximab + radioterapia vs. estándares de atención en pacientes con carcinoma de células escamosas de cabeza y cuello localmente avanzado. CheckMate-651: Estudio fase III, aleatorizado y multicéntrico, que evalúa nivolumab + ipilimumab vs. el régimen EXTREME (cetuximab, cisplatino/carboplatino y fluorouracilo) como tratamiento de 1L en pacientes con carcinoma de células escamosas de cabeza y cuello con recurrencia o metástasis, elegibles para platino. KEYNOTE-048: Estudio fase III, aleatorizado y abierto, que evaluó pembrolizumab + quimioterapia o monoterapia con pembrolizumab vs. el régimen EXTREME, como tratamiento de primera línea en pacientes con cáncer de cabeza y cuello escamoso recurrente o metastásico. COSMIC-311: Estudio fase III, doble ciego, en pacientes con cáncer diferenciado de tiroides refractario (>16 años) que experimentaron progresión radiográfica durante o después del tratamiento con hasta 2 inhibidores multicinasas de VEGFR previos que debían haber incluido lenvatinib o sorafenib. MERAIODE: Estudio fase II, de rediferenciación con trametinib seguido de yodo radiactivo para pacientes con cáncer de tiroides diferenciado refractario al yodo radiactivo metastásico con mutación de RAS. ELDERLY: Se inscribieron a pacientes que tenían al menos 65 años y tenían carcinoma de células escamosas de cabeza y cuello en estadio III-IVb y eran potencialmente adecuados para el tratamiento curativo. Entre diciembre 2017 y marzo 2021 el estudio inscribió a 101 pacientes (33.7% en forma, 39.6% vulnerables y 26.7% frágiles). Después de la evaluación geriátrica, la estrategia terapéutica principal se cambió en 12 pacientes (11.8%), en particular en 7 se desintensificó, en 4 se intensificó y en uno cambió de cirugía a quimio-radiación.

In this podcast, Veerle Lamotte, an oncology nurse practitioner at Antwerp University Hospital and Paola Belardi, nurse chief at San Donato Hospital in Arezzo, Italy discuss the role of the nurse in the management of adverse events in patients receiving VEGFR-TKI treatment. Their discussion focuses specifically on patients with hepatocellular cancer (HCC), differentiated thyroid cancer and advanced renal cell carcinoma (RCC). VEGFR-TKIs are widely used treatments for these solid tumours but are associated with substantial toxicity which needs early recognition and management in order to help patients stay on optimal treatment. The most common adverse events related to these treatments are discussed together with recommendations for their management. Veerle and Paola discuss the key role of the nurse as part of the multi-disciplinary team involved in the patient’s care, and the role they have in providing close support and guidance to the patient. Education of patients regarding potential side effects and early identification and management of adverse events is key in terms of trying to keep patients on the optimum dose so that they can achieve the best outcomes.

Dr. Jaume Capdevila, a Medical Oncologist at Vall d’Hebron University Hospital in Barcelona, Spain, and Dr. Rachel van Leeuwaarde, an Endocrinologist from the University Medical Center of Utrecht in The Netherlands discuss the use of multi-kinase inhibitors (MKIs), in particular VEGFR-TKIs in patients with radioactive iodine refractory differentiated thyroid cancer (DTC). In this podcast, the two experts discuss key trials (SELECT, DECISION and COSMIC-311) and efficacy parameters of the current VEGFR-TKIs (lenvatinib, sorafenib and cabozantinib), how to manage toxicity whilst trying to optimise treatment outcomes and preserving always patients’ quality of life. They also discuss treatment strategies, when to start systemic treatment, which drug should be used first and how to sequence therapies. To close the podcast they take a look at ongoing clinical trials with other treatments in development for DTC.

Dr. Michael McCullar, CEO, and Dr. Hong Tang, Chief Medical Officer at OnQuality Pharmaceuticals, a clinical stage pharma company pioneering the discovery and development of targeted cancer supportive care therapies that address cancer treatment-related toxicities at the molecular level, discuss the company's lead pipeline candidate, OQL011, the first targeted treatment for the severe cancer med side effect Hand Foot Skin Reaction (HFSR). OQL011 is currently in Phase 2 study at onco-dermatology clinics across the country. It is a topical ointment that can be applied to the hands and feet, acting locally to restore VEGFR signaling while avoiding any interference with the main cancer med mechanism of action. Michael McCullar is the Chief Executive Officer of OnQuality Pharmaceuticals. He has more than 20 years of pharmaceutical experience in strategic planning and development, drug discovery and operation, business development and commercial operation. Previously he served as Chief Operating Officer at Tolero Pharmaceuticals, where he oversaw drug discovery and development activities as well as corporate development, and commercial planning. He played a major role in the acquisition of Tolero by Sumitomo Dainippon Pharma for $780M ($200M upfront). Prior to joining Tolero Pharmaceuticals, he held multiple roles at Astex Pharmaceuticals including Senior Vice President of Business Development where he was involved in the acquisition of Astex Pharmaceuticals by Otsuka for $886M in cash. In addition, he served as Vice President of Development and Operations and led the FDA approval of Dacogen for the treatment of MDS, while at SuperGen, Inc. Dr. McCullar earned a PhD from the University of California and an MBA from the W.P. Carey School of Business, Arizona State University. Dr. Hong Tang, Chief Medical Officer, and co-founder of OnQuality Pharmaceuticals. Hong is a Board-certified physician with more than 15 years' experience in both drug development and medical affairs, and conducted all phases of clinical trials. She served as VP, Executive Medical Director, Medical Director, and Medical Officer in Dendreon, Juno, Astellas, BMS and NIH. #OnQualityPharmaceuticals #OQL011

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Dr. Jason Luke, associate professor and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center, discusses new advances in immunotherapy that were discussed at the #ASCO20 Virtual Scientific Program.   TRANSCRIPT ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Joining me today is Dr. Jason Luke, associate professor and director of the Cancer Immunotherapeutics Center, at the UPMC Hillman Cancer Center.   His clinical focus is on immunotherapy for advanced solid tumors, as well as cutaneous malignancies and melanoma. Dr. Luke will discuss key abstracts in the immunotherapy field that were featured at the ASCO20 Virtual Scientific Program, including Abstract 3004, the study of an agent called MGD013, which Dr. Luke presented during the meeting. Dr. Luke, it's great to have you on the podcast today.   Dr. Jason Luke: Thank you very much.   ASCO Daily News: Do you have any conflicts of interest to disclose that are relevant to the issues we'll discuss in this podcast?   Dr. Jason Luke: Thanks. I would like to disclose a few things. I'll note that as a phase I clinical trialist, I try to work with every company in the field. But relevant to the abstracts, I have been a consultant to most of the big pharmas that have advanced these. So specifically, EMD Serono, Genentech, EMS, Merck, and some others.   ASCO Daily News: Dr. Luke, are there any advancements in the immunotherapy field that will likely support new standards of care?   Dr. Jason Luke: So thank you. Yes. In fact, this was a big year for immunotherapy. I think ranging from abstracts with a high immediate impact on the standard of care all the way to -- or earlier truly -- research studies that I think we'll look back on and realize this was the year when that technology started to mature.   So when thinking about abstracts-- presentations that are going to have an immediate impact on the standard of care, there are really two that I would highlight. One of them was called the JAVELIN Bladder 100 trial (Abstract LBA1). And the second one was a clinical trial called KEYNOTE 177 (Abstract LBA4). So I'll talk about them individually at first. And I think they introduce ideas about using immunotherapy you should be cognizant of to inform your practice.   So for the first one, the JAVELIN Bladder 100 trial, is a clinical trial in advanced urothelial cancer, in which patients were treated in the frontline setting, albeit for that first treatment and the standard of care setting, with cisplatin-based chemotherapy. And as they completed their cisplatin-based chemotherapy, they were randomized to either get the anti-PD-L1 antibody, avelumab in a maintenance sort of approach, or waiting until they had progression and going on to standard therapy with second line chemotherapy, as would be commonly done.   So the clinical trial showed an overall survival advantage to the maintenance approach of giving avelumab or anti-PD-L1 in that setting. And this is a pretty big deal because this is really the first maintenance approach that really has been associated with an overall survival advantage in solid tumors in general, but specifically a bladder cancer.   Now obviously the context for such an approval is the activity of PD-1 or PD-L1 blocking agents in urothelial cancer. And probably everyone who is listening is aware that multiple checkpoint inhibitors are approved for second line usage in bladder cancer. And all of you listening are probably also aware that there's been a lot of discussion in the field of urothelial cancer about moving checkpoint inhibitors into the frontline setting.   And the FDA had to release a guidance that that should not be done without the obvious presence of PD-L1 positivity. So a very interesting thing from the JAVELIN Bladder Trial was that the benefit to maintenance avelumab appeared to be independent of PD-L1 status. So in other words, everyone, or the total population of patients, benefited from getting that chemotherapy and then going on to get avelumab, whether PD-L1 positive or negative.   So I think that's a big deal. So based on these data my read of it and the conversations that I've had with other experts in the field of GU malignancies aren't to suggest that this is a new standard of care, that patients should after completing initial chemotherapy go on to get a PD-1 or PD-L1 agent.   Now that being said, it isn't without some controversy. These maintenance approaches have been criticized over time about cherry picking patients and discontinuing chemotherapy that might otherwise be active. One can't really know here how many patients would have done well without the avelumab for a long time.   It's also obviously the case that patients could go on to get second line PD-1 or PD-L1 agents on label. So again pembro, nivo, atezo, durva, avelumab, these are all approved for second line therapy. And in this clinical trial, because it was done ex-US, only about 40% of the patients who were on the placebo-matched arm actually went on to second line PD-1.   So this trial definitely did not test the question of maintenance PD-1, PD-L1 versus giving it in the second line after an initial progression event in the front line. And that is obviously a criticism of these data. Now that being said, all of you who have treated patients with urothelial cancer realize what an aggressive malignancy this can be and how these patients can sometimes be rather frail.   And what we can run into is that at the time of progression after frontline chemotherapy performance statuses just dwindle very rapidly, such that you can't really, fully give them a shot to get the second line PD-1 immunotherapy. So here, though, by giving the therapy immediately after the initial chemotherapy without waiting for progression, we make sure that all patients get access to that therapy.   So despite the controversy around subsequent lines of therapy, et cetera, I think most people who view this data really do find it to be practice changing. And moving forward we really should be considering immediate initiation of anti PD-L1, or PD-1 I suppose, after chemotherapy. So that was the first abstract to highlight in that space, the JAVELIN Bladder 100 study.   The second study was the KEYNOTE 177 study (Abstract LBA4). This was a randomized phase III trial in the frontline setting for MSI-- or MicroSatellite Instable-- colorectal cancer for the use of immunotherapy with pembrolizumab, as opposed to chemotherapy. And so again oncologists listening will be very well aware that MSI status has become an important biomarker in our field, selecting out patients, especially with colorectal cancer but actually any cancer type, who if they have MSI status can be treated in this integrative care setting with the anti-PD-1 or pembrolizumab.   One of the questions that has been looming and seemed like had an obvious answer, and, in fact, this trial supports, was whether that biomarker would be strong enough to move that immunotherapy into a prechemotherapy setting. So to date the use of the MSI biomarker has been to select patients after they failed standard therapies to go on to get immunotherapy.   So in colorectal cancer, patients would get FOLFOX/FOLFIRI as per standard. And if they were MSI, they would be treated thereafter with pembrolizumab. So in this study, they moved that biomarker selection into the frontline, looking at MSI high patients and randomizing them to either get pembrolizumab or standard chemotherapy.   And the answer here, as was expected, was that patients who are MSI high in their tumor who got immunotherapy in the frontline, in fact, did better than those patients who got chemotherapy in the frontline. And so I think that's an important clinical practice changing algorithm. So we should be testing all our patients upfront for MSI with colorectal cancer, and one might even argue actually other tumor types, because we find that the patients who have that phenotype, their rates of response approach 50%.   And those responses tend to be very durable with the median not being reached in these kinds of trials. So that quality of immunotherapy response, I personally think that's the thing that we all really like about immunotherapy, is that for the small patients where they get that benefit from immunotherapy, it can sometimes be long lasting-- and even life lasting-- kind of benefit. I think these data are very important, again, to move this biomarker selection of patients for colorectal cancer by MSI high status into the front line and give them immunotherapy if we find that.   These data don't come as much of a surprise given that we know in the adjuvant setting, in fact, the MSI high patients do worse with chemotherapy in the stage two setting. So again, these data don't come as a big surprise. But they do support a change in practice to move immunotherapy into that frontline setting.   And I would say as a sort of forward-looking discussion point, given the broad approval across cancer types for MSI high tumors to get pembrolizumab, one wonders whether or not this phenomenon will begin to come forward and other tumor types where we know MSI could be present, such as gynecological cancers and some others. We'll watch the field. But I think that that's something to be excited about for immunotherapy coming forward and potentially displacing chemotherapy in the front line for different cancer types.   ASCO Daily News: Dr. Luke, what are the other studies that really stood out for you this year?   Dr. Jason Luke: There were three other big trials I think that generated a lot of buzz that I think I should be highlighted. They don't quite change standard of care at this time. But they do influence standard of care.   And so there are three of them. One of them was the CHECKMATE-9LA study of lung cancer (Abstract 9501). There was a second phase 2 study called the CITYSCAPE study (Abstract 9503), also in lung cancer. And a third study in bladder cancer called the IMvigor010 (Abstract 5000) or 10 study.   So just to discuss them-- so CHECKMATE-9LA in fact did lead to an FDA approval of the combination of nivolumab and ipilibumab or PD-1 CTLA-4 in combination with chemotherapy for the frontline management of non small cell lung cancer. So this regimen is somewhat different than the chemo I-O combo that people will be cognizant of right now. So the standard of care now, there's an approval for chemotherapy with platinum-based chemotherapy and a second agent, such as pemetrexed, with pembrolizumab in the front line.   This trial took a different tact. And they randomized patients to either get regular chemotherapy, platinum-based chemotherapy, or they would get the combination of ipi and nivo with two cycles only of platinum-based chemo. So you could refer to this as some sort of platinum sparing approach. And the rationale for this was that perhaps because patients with lung cancer can have a very aggressive course, having that immunotherapy onboard up front might allow a space for immunotherapy then to kick in and have a longer term benefit.   So this trial is a positive Phase III clinical trial. And actually just before the ASCO virtual meeting, the FDA approved this regimen for the use in patients with lung cancer. Now you might be listening and thinking, well, wait a minute. You just told me about their new standards of care. And you're telling me this is approved. So what's the deal?   And so what the deal is is that it's not completely clear at this time that this sort of an approach would be better than using the chemo pembro combination that's already approved. And the toxicity profile using doublet checkpoint blockade with PD-1 and CTLA-4 is not insignificant. Sorry for the double negative there. But in other words, you're generating a lot of immune-related side effects for patients by giving them ipi/nivo and chemotherapy.   So the question then becomes, so which patients then should you give chemo pembro to versus giving chemo ipi/nivo to? And unfortunately at this time, we don't really know the answer to that question. So that then sets us up with a tough spot to sit in, that we don't really know how to use these regimens either way. And we know one of them causes more side effects.   So what I would say right now is that it's not clear that this advances the field in terms of changing the standard of care. But I'll be very interested to see the long-term outlays in terms of overall survival in this clinical trial. So the trial we would want to see would be chemo pembro versus chemo plus ipi/nivo.   But these trials were done chronologically at similar times. And the standard of care had not switched to chemo pembro yet when they had started this trial. So certainly that's a future trial we would look forward to. I think it is possible that the chemo ipi/nivo trial might have the potential to have better overall survival over a long period of time, relative to chemo pembro.   And the reason I say that is we can see that in melanoma where giving ipi and nivo does appear to give better longer overall survival, but you don't see that effect until about two to three years after you start ipi/nivo relative to starting nivo monotherapy. So we're not really going to know whether or not the long term survival of this quadruplet regimen of platinum doublet plus ipi/nivo is actually better than the triplet of platinum doublet plus pembro.   We're not really going to know that in a head-to-head trial for a long time. And even just comparing two trials head-to-head, we're not really going to know that again for at least a couple of years. So I don't know whether or not that trial really changes practice yet. But it'll be very interesting to watch it over time.   The second trial I wanted to talk about that really stood out was the CITYSCAPE trial (Abstract 9503). And so this is a nice name for a clinical trial. Essentially what it is is looking at a combination immunotherapy in the PD-L1 high subset of non small cell lung cancer. So in patients with greater than 50% TPS In lung cancer, the molecule, the PD-L1 antibody atezolizumab, was combined with an anti-tigit antibody in that population and randomized against atezolizumab plus a placebo.   And the idea here would be to look for a second combination checkpoint that's not CTLA-4 and see if that could have more activity relative to a PD-1 PD-L1 monotherapy in that PD-L1 high population. So again, all of you are aware that PD-1 monotherapy is approved in that setting. PD-1 and PD-L1 are both approved for PD-L1 high patients in frontline lung cancer.   And what they observed in this CITYSCAPE study was an improvement in the response rate for the combination immunotherapy relative to the PD-L1 plus placebo. And that was statistically significant. And it was of substantial interest.   So I think that's very interesting. And based on those data, in fact, the company advancing this tigit antibody that makes atezolizumab has rushed forward into a series of randomized Phase III clinical trials, where they're combining atezolizumab with this tigit antibody across a number of diseases. The first two trials will be a non small cell lung cancer as well as small cell lung cancer with the idea that this new PD-L1 plus tigit regiment essentially is going to replace a PD-1 or PD-L1 monotherapy either as-- oh, sorry, either as monotherapy or in combination with chemotherapy and various different indications.   So this is really interesting because the toxicity profile of this combination regimen was quite modest and in fact look mostly like a PD-1 PD-L1 monotherapy. So this wouldn't be the addition of a second checkpoint that actually doesn't increase the toxicity, but might amplify the benefit. And so why would that be the case?   Well the checkpoint tigit we know from basic biology is also associated with the T cell activation state in the tumor microenvironment. And it may very well be that this is yet another checkpoint that's important in the tumor, that by blocking it we might not increase the overall toxicity because where the tumor is where the action is at. And it might increase the benefit.   And that would be different than CTLA-4 or ipi, where the effect is broadly throughout the whole body and not localized in the tumor microenvironment. So that's a very interesting molecule, this tigit molecule to keep your eyes on, because I think there will be a number of Phase III trials coming forward the next few years It'll be very interesting to see if we can find other combination immunotherapies.   The third abstract that I wanted to dwell on quickly that stood out-- again, doesn't change practice, but it's important to be cognizant-- was IMvigor 10 or 010 (Abstract 5000). And this was a bladder cancer randomized Phase III adjuvant clinical trial. And the idea was high risk patients with bladder cancer are randomized to either get atezolizumab or to get placebo in the adjuvant setting.   And really as, I have to say, a shock to most of the people in the field, there was no difference in rates of relapse or overall survival in high risk urothelial cancer for patients who got adjuvant PD-L1 relative to those who got placebo. And this is one of those things where don't count your checks before they're cashed, or don't count your eggs before they're cracked, or whatever the euphemism goes. Everyone assumed this would be a positive clinical trial.   In melanoma when we moved PD-1 antibodies from the metastatic setting into the stage three setting, it was a slam dunk. It was fabulous, unbelievable-- hazard ratio of 0.5. Yet here we see in another disease, which is responsive to immunotherapy in the refractory disease setting, we see no difference in the adjuvant setting. So I think that's really an eye opener and, again, just suggests why we have to do these trials.   My dad used to like to say, that's why they play the games. Let's talk about sporting events with atypical outcomes, things you didn't expect. So that's again what we saw here. So adjuvant PD-1 or PD-L1 is not a standard in bladder cancer. There are some other clinical trials that are ongoing to look at other PD-1 agents that have slightly different designs. And we'll be very interested to see what the results of those kinds of clinical trials look like over time.   ASCO Daily News: Are there any other clinical trials that our listeners should be aware of?   Dr. Jason Luke: Yes, so there are also a whole handful of trials that I think are worth quickly pointing out because I think they give us indications around better using agents that we already have. So in melanoma there were a couple of abstracts presented that looked at the use of CTLA-4 with a PD-1 in second-line melanoma. So in patients who got a frontline PD-1 an open question is, should you give them ipi as the second line, so PD-1 followed by CTLA-4? Or what about the idea of continuing the PD-1 and adding the CTLA-4 antibody on top of it?   And so there were two abstracts. There was a prospective open label Phase II study, in fact, that I designed. It was our study (Abstract 10004). And what that showed was that where we would expect a response rate of about 13% to ipilimumab in the second line as a monotherapy, in our Phase II study of 70 patients, we got a 27% response rate. And that trial was augmented by another abstract from the Melanoma Institute of Australia, who aggregated their experience of what they had done in their standard practice in the second line.   And in the patients who had gotten ipilimumab plus nivolumab after a PD-1 (Abstract 10003), they observed a 32% response rate. So if you put these two studies together, you're now up about 250 patients between both series. And you get a response rate between both of them around 30%. And that looks to be about a doubling of what we would expect in standard care setting of just getting ipi monotherapy after PD-1.   So I think that's a really interesting thing to be aware of. In my practice I tend to give that combination regimen after initial PD-1. And I think we'll look forward to a study from SWOG, which is actually randomized patients to get ipi/nivo versus just ipi after a frontline PD-1. So I think that's a really important abstract to be aware of.   The other study that I'll be-- but I'll just share, however, was that in contrast to that, there was a series of studies presented in renal cell carcinoma, where this paradigm did not appear to be true. So there was an abstract called the FRACTION study in renal cell carcinoma (Abstract 5007), as well as the Hoosier Oncology Group GU16-260 (Abstract 5006). In both of those studies, there did not appear to be a big benefit to adding ipi after a patient had progressed on PD-1.   And that was interesting because in the FRACTION study (Abstract 5007), they used ipi/nivo. And they got responses in the second line. But in the Hoosier study, it was less clear. And so I think the renal guys feel like if you're going to use ipi/nivo, you need to do it right away upfront. And you shouldn't do the sequential approach of giving a PD-1 and then adding on ipi later.   And it's interesting to contrast those two things because that's a difference between tumor types, where we think there might be more benefit to giving that combination or waiting for the combination of melanoma, whereas in renal, if you're going to use it, you should really come in guns blazing both checkpoints at the same time.   One other study I want to do just highlight quickly was also in melanoma, where the group from Sloan Kettering did a study looking at two doses of ipi/nivo versus four doses of ipi/nivo. And not to dwell on it too long, but what they observed was essentially all of the benefit and all of the toxicity appeared to be associated with just the first two doses of ipi/nivo.   In other words, when they looked at an early CT scan to look for responders, all the responding patients had already basically had their benefit after the first two doses. And none of the patients who hadn't already benefited by two doses actually went on to benefit at four. So this was a pretty small study. It was upwards about 25 or 30 patients. But I think this really deserves further follow up.   And I think it emphasizes, however, that in clinical practice, there is no need to really push the envelope in giving more ipi/nivo, especially if patients have toxicity. So if patients get a couple of doses and they get toxicity, you do not need to go back to pushing them to get more doses. We'll be very excited to look for future data to really look into this so we can really optimize the use of combination immunotherapy in the broader population.   ASCO Daily News: Dr. Luke, are there new treatment approaches or agents in development that you are particularly excited about this year?   Dr. Jason Luke: Yes, so there were, as I mentioned, a couple of abstracts around adoptive cell therapies in solid tumors that I think we're going to look back on this year's ASCO and say, wow, this is the year when these things really started coming to the forefront. And there were three of them that I'll highlight quickly.   One of them is a drug called lifileucel. In fact, that is a tumor-infiltrating lymphocyte product. And in melanoma, an updated data series was presented on a group of about 70 patients who had undergone tumor excision and then harvesting of TIL. And then a TIL product was made. Patients were given lymphodepleting chemotherapy and were reinfused their TIL . (Abstract 10006)   And what was exciting about it was the stability of these results over time. So in these patients, a response rate in 70 patients was observed at 36%. And realize that these are patients who already had PD-1. They had CTLA-4. They had BRAF. These were refractory patients. So a 36% response rate-- quite impressive.   The other thing that was very interesting to be observe was that the duration of those responses in the refractory disease setting was not reached. So in other words, the patients who responded did very well. And then the final thing on that one to be aware of was it looked like patients who would benefit from that therapy were disproportionately those who had not benefited from previous PD-1 therapy.   And certainly, that's a big unmet need in melanoma. And in the melanoma field, we're fairly confident that this therapy is going to be approved by the FDA either later this year or next year. So being cognizant of cell therapy for solid tumors, at least in terms of TIL for melanoma, is going to be important.   The other two abstracts I'm going to put together quickly. One of them was about SPEAR MAGE-A4 TCR transduced T cells (Abstract 102), as well as a second abstract about HPV E6/E7 TCR transduced T cells (Abstract 101). So what are TCR transduced T cells, you might ask?   What this is, is taking a patient's own lymphocytes and then ex vivo transducing them with a lentiviral vector most commonly to express a T cell receptor that's been identified from a different patient. So that T cell receptor can be specific for a certain antigen. So you'll have heard-- I mentioned MAGE-A4-- as well as HPV E6/E7.   So these are antigens that we know can be expressed to certain degrees in certain tumor types. For example, MAGE-A4 is highly expressed in sarcomas as well as some esophageal cancers. And HPV is obviously highly expressed in HPV-associated cancers, such as cervical cancer and others-- head and neck, et cetera. And so these studies were very interesting because obviously this is a somewhat complicated process, sort of like the TILs I told you about before, but it adds an extra layer of genetically modifying the product.   But, again, they saw high levels of response in tumor types that had these antigens. And those responses tended to be durable over time. So there are randomized trials coming forward now to look at these agents. And I'm very excited that over the next couple of years, we're really going to see a movement of cell therapies to the prime time and maybe even in the standard of care setting for patients with multiple solid tumors.   ASCO Daily News: Absolutely. Can you tell us about new agents that will likely move the field forward or have already done so?   Dr. Jason Luke: Yes, so there were a handful of abstracts here. But I think there are two conceptual things that I'm going to highlight. It isn't so much the individual agents, I would say, but rather the concepts around them. I'll give you the names of the agents so you can look them up.   But one of them was an agent called MGD013 (Abstract 3004). But the reason it's of interest is that it's a bispecific antibody. So disclosure, I was the presenter of this abstract. But I think it's very interesting because what it gets at is a future of using antibody engineering technology to bring forward novel agents. So MGD013 is a bispecific PD-1 and LAG-3 inhibitor.   So those are two immune checkpoints that are being investigated separately with monoclonal antibodies. But here we have one drug that can hit both of those. And so what was interesting was the drug was safe. And the response was seen across a host of different diseases.   But perhaps most interestingly in the trial, we combined MGD013 with the HER-2 antibody margetuximab. And margetuximab is an FC-modified and optimized HER-2 antibody. And in patients who had refractory HER-2-positive tumors that were PD-L1 and LAG-3 low, the combination of MGD013 with margetuximab generated more than 40% treatment responses.   So this really fits the paradigm of what we were hoping to do. And you may have heard of this-- "turning cold tumors hot" is how we sometimes talk about this. In other words, we can identify a biomarker, target that with the margetuximab in HER-2, and then come in with immunotherapy. And because the first therapy was successful, it makes the second therapy likely to be successful as well.   So I would be aware of these bispecific approaches. Some of them have come forward from leukemias already. And I think in solid tumors, it will be interesting as well.   And the final one I'll note were the combinations of VEGF or VEGFR inhibitors with PD-1s or PD-L1s. And in fact there were so many of these combinations presented that I don't really have time to go over all of them. The listenership will be cognizant that the standard of care has changed in kidney cancer and recently in hepatocellular carcinoma in the front line to include these kinds of combinations.   But there were data presented for endometrial cancer (Abstract 6083), mucosal melanoma (Abstract 10040), colorectal (Abstract 4019), bladder (Abstract 5013), prostate (Abstract 5564), lung (Abstract 9610), more, that these combinations look to be quite active in the PD-1 progressed setting. And in fact clinical trials are now starting to move these combinations into earlier lines of therapy as well. So I think this combination of VEGF blockade with PD-1 is really going to be something to be on the lookout for because I think this is going to expand the horizon of immunotherapy within and across multiple solid tumors.   ASCO Daily News: Excellent. Thank you, Dr. Luke. So I'd like to let our listeners know that the abstract numbers relating to all of the studies Dr. Luke discussed today are on the transcript, which is published with this episode. Dr. Luke, thanks again for your insights on these incredible developments in the immunotherapy field.   Dr. Jason Luke: Thank you very much for having me, Geraldine.   ASCO Daily News: Thanks to our listeners for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us on Apple Podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

[MUSIC PLAYING] ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Kara Nyberg. Joining me today is Dr. Emily Bergsland, who is a GI medical oncologist and professor of medicine at the University of California San Francisco. Welcome to the podcast, Dr. Bergsland. We're here to discuss highlights from the 2020 Gastrointestinal Cancer Symposium, for which you served as the program chair. Let's begin with research presented at the meeting that has a direct bearing on clinical practice. Are you and your colleagues going to change your practice based on data coming out of this symposium? And if so, how? Dr. Bergsland: There were a couple of important advances reported at the meeting that are likely to support new standards of care moving forward. We know that BRAF V600E mutated metastatic colorectal cancer is associated with a very poor prognosis. The BEACON trial was a randomized phase III study of encorafenib plus cetuximab, with or without binimetinib, in previously treated BRAF mutant metastatic colorectal cancer. The BEACON investigators had previously reported that triplet therapy seemed to be better than doublet therapy and improved survival and response rates compared to standard of care treatment. Dr. Bergsland: At ASCO GI, Dr. Kopetz presented updated results showing that encorafenib plus cetuximab, with or without binimetinib, demonstrated longer maintenance of quality of life, and there was no difference in the quality of life benefit between the doublet and triplet regiments. Furthermore, the median survival is now the same in both groups, 9.3 months, which is significantly better than the 5.9 months seen in control. As a result, the study team is moving forward with doublet therapy instead of triplet therapy, and this filing is now under review by the FDA. Dr. Bergsland: Updates to the IMbrave150 study were also reported. The IMbrave150 study was a randomized phase III trial of atezolizumab plus bevacizumab versus sorafenib as first line treatment for unresectable hepatocellular carcinoma. As reported at ESMO Asia, atezolizumab improved overall in progression-free survival compared to sorafenib. At ASCO GI, the study team reported that atezolizumab was also associated with significant and consistent benefits in quality of life, functioning, and key symptoms, providing further support for atezolizumab as a new standard of care for untreated hepatocellular carcinoma. Dr. Bergsland: Finally, the results of a randomized phase II trial of gemcitabine and cisplatin, with or without the PARP inhibitor veliparib, in patients with pancreatic cancer and germline BRCA or PALB2 mutations were presented. Surprisingly, both arms were highly active, with an overall response rate of 74% with triplet therapy and 65% with chemotherapy alone. Olaparib added little benefit, possibly because of heme toxicity limiting the dose delivered. But the high response rate and overall survival of 15 to 16 months in both groups provide support for gem/cis as a new reference treatment for pancreatic cancer in patients with germline BRCA or PALB2 mutations. ASCO Daily News: Are there any new treatment approaches or agents in development that you're particularly excited about? Dr. Bergsland: Several presentations focused on biomarkers and liquid biopsies in particular, which I think is where the field is going. The potential value of circulating tumor DNA to guide therapy was highlighted by a study presented at GI ASCO comparing tumor tissue genomic profiling to plasma circulating tumor DNA sequencing using the SCRUM-Japan GI screen and GOZILA combined analysis. Dr. Bergsland: Investigators found that plasma genotyping significantly reduced turnaround time compared to tumor tissue, 35 days versus 12 days, and led to a shorter interval between genotyping and enrollment to match trials. Dr. Bergsland: There are many prospective clinical trials incorporating circulating tumor DNA underway to validate the use of liquid biopsies to guide treatment, monitor for resistance in GI malignancies, and assess for minimal residual disease after resection, an example of the latter being the COBRA study for stage II colon cancer. Expanding on the idea of blood-based biomarkers, Brian Mulpin described development of a methylation-based cell-free DNA early multi-cancer detection test that can also predict the tissue of origin. Samples were collected as part of the circulating cell-free genome atlas in individuals with and without different cancers. Dr. Bergsland: Plasma cell-free DNA was subjected to a cross-validated targeted methylation sequencing assay, and the study included both training and validation data sets. The data suggests that a targeted methylation assay from cell-free DNA in the blood may represent a novel non-invasive way of detecting different GI cancers and identifying site of origin. Finally, another interesting finding relates to the fact that identification of the optimal duration and type of adjuvant therapy for patients with resected colon cancer remains a challenge. Dr. Bergsland: The Immunoscore, which measures immune infiltration in tumors, has emerged as a prognostic marker for patients with localized colon cancer. At ASCO GI, researchers presented an analysis of the Immunoscore in modified FOLFOX-6 treated patients enrolled in the France cohort of the idea study. The results confirm that the Immunoscore is prognostic in these patients. Interestingly, only patients with Immunoscore intermediate or high benefited from six months of FOLFOX treatment compared to three months. Dr. Bergsland: This was true in both clinical low and high risk subgroups with stage 3 disease. This means that Immunoscore low patients not only have a higher risk of relapse, but they have no obvious benefit from six months of FOLFOX compared to three months. Validation of the results in an independent cohort is planned, but the findings could represent an important step towards improving our ability to individualize adjuvant chemotherapy in patients with resected stage 3 colon cancer. ASCO Daily News: I know that immunotherapy with checkpoint inhibitors has captured much of the limelight in recent years. Were there any new and notable findings with regard to these therapies? Dr. Bergsland: Given the IMbrave150 results showing the value of atezo-bev in first line hepatocellular carcinoma, the CheckMate 040 study results are of interest. This was a study of 71 patients with advanced hepatocellular carcinoma randomized to receive nivolumab plus cabozantinib, with or without ipilimumab. Radiographic responses were seen in both groups, 19% with the doublet and 29% with the triplet, and a high disease control rate was observed in both arms. Overall survival after two years of follow-up was at least 22 months in both arms. Dr. Bergsland: The triplet regimen was associated with more toxicity. Additional studies integrating safety, efficacy, and patient reported outcomes will be needed to determine the relative value of either of these regimens compared to other treatment options for hepatocellular carcinoma. Updated CheckMate 142 data were also presented regarding the use of nivolumab plus low-dose ipilimumab as first line therapy in MSI-high metastatic colorectal cancer. Nivolumab, with or without ipilimumab, is already FDA approved for chemotherapy-resistant MSI-high metastatic colorectal cancer, but the role of combination therapy in the first line setting is unknown. Dr. Bergsland: CheckMate 142 included 45 previously untreated patients with MSI-high or defective mismatch repair metastatic colorectal cancer. At a median follow-up of 20 months, the overall response rate is 64%. The median overall survival and progression-free survival have not been reached. Combination therapy was well tolerated. This may represent a new first line treatment options for these patients, but longer follow-up is needed to see if the high response rate translates into improved overall survival. ASCO Daily News: Interesting. Let's move now to earlier stage disease. What advances were discussed related to the treatment of localized GI malignancies? Dr. Bergsland: There were several presentations focused on the treatment of localized disease, and the theme seemed to be that less may be more. In terms of surgical questions, Dr. Yamada presented preliminary results from the TOP-G trial, a randomized phase II study showing that omentum-preserving gastrectomy is associated with similar short-term outcomes compared to standard of care gastrectomy with omentectomy. The results are not definitive, but support enrollment to an ongoing phase III study, JCOG1711, which would provide a definitive answer on the role of omentectomy. Dr. Bergsland: In another randomized study, extensive peritoneal lavage did not improve survival compared to surgery alone. This is not recommended for patients undergoing curative gastrectomy for cancer. Finally, researchers from Japan reported on the results of the randomized phase III iPAC study. Primary tumor resection followed by chemotherapy did not improve overall survival compared to chemotherapy alone, thus can't be routinely recommended for colorectal cancer patients with an asymptomatic primary tumor and synchronous unresectable metastases. 87% of patients in the control arm were able to avoid surgery. Dr. Bergsland: In terms of adjuvant therapy, the RESONANCE trial assessed the use of perioperative SOX chemotherapy in patients with resectable gastric cancer in China. 772 patients were randomly assigned to receive pre- and post-op SOX or adjuvant therapy alone. Neoadjuvant SOX was associated with a higher R0 resection rate, acceptable adverse event profile, and no differences in short-term outcomes. The primary endpoint of three-year disease-free survival has not been reached, though, so this approach remains investigational. Dr. Bergsland: The results of CCOG-1302 were also presented, a randomized phase II trial assessing CAPOX with continuous versus intermittent use oxaliplatin as adjuvant chemotherapy for stage 2 and 3 colon cancer. CAPOX with planned intermittent oxaliplatin substantially reduced long-term peripheral sensory neuropathy in patients treated with six months of adjuvant therapy, and three-year disease-free survival was similar between groups. Dr. Bergsland: While intriguing, the results are not practice-changing, as it was a relatively small phase II study. Finally, the Dutch Art-Deco phase III study showed that radiation dose escalation, up to 61 gray to the primary tumor, increased toxicity without increasing local control or overall survival compared to standard dose radiation in patients with esophageal cancer receiving definitive chemoradiation. ASCO Daily News: The theme for the GI Cancer Symposium this year was accelerating personalized care. Based on research presented at the meeting, what is the field currently doing well, and what can the field be doing better? Dr. Bergsland: Generally speaking, I think we're making significant progress. One big area of study relates to identification of patients at risk for GI malignancies and modifying cancer screening guidelines accordingly. For example, there was a session on screening in high risk populations. Providers should offer germline testing to any patient with a personal history of pancreatic cancer, since approximately 10% of patients will have an inherited germline mutation. Dr. Bergsland: Guidelines for screening continue to evolve, but their emerging data support the use of MRI or EUS in mutation carriers. Cholangiocarcinoma rates are increasing globally, and we know that the risk factors vary by location and that type 2 diabetes, a non-alcoholic steatohepatitis, or NASH, may also be contributing. NASH cirrhosis is also a risk factor for hepatocellular carcinoma. Screening practices are evolving as our recommendations for chemo prevention, which may include aspirin and statins in high risk patients. Dr. Bergsland: Another important area is early onset colon cancer. Colorectal cancer incidence has been declining for several decades in people over the age of 55, but rates in people younger than 55 are increasing at nearly 2% annually, and this has been ongoing since 2006. Younger patients present with more advanced disease and more poorly differentiated tumors. As such, there's an ongoing debate surrounding the optimal age to start screening. Better colorectal cancer risk prediction tools are needed. In the meantime, high risk groups should be prioritized, such as those with a family history of cancer, inflammatory bowel disease, or polyps. Dr. Bergsland: In addition to improvements in our identification of high risk patients, we're also making great strides in translating advances in our understanding of the molecular underpinnings of GI malignancies to the clinic. The BEACON data are certainly encouraging with respect to the treatment of BRAF V600E metastatic colorectal cancer, and the molecular basis for cholangiocarcinoma is now much better understood, with biomarker-based trials now available for FGFR and IDH-mutant cancers. Despite the many advances presented at the meeting, though, there were a few disappointments, suggesting that there's still a lot of work to be done in the area of biomarker selection and drug development. Dr. Bergsland: The HALO-109-301 study of nab-paclitaxel/gemcitabine, with or without PEGPH20 in patients with previously untreated hyaluron-high metastatic pancreatic ductal adenocarcinoma was a negative study in a biomarker-selected population. There were also several negative studies in biomarker-unselected patients. The SEQUOIA study of FOLFOX with or without pegylated interleukin-10 as second line therapy for metastatic pancreatic cancer was negative, and there was no benefit in adding ramucirumab, a VEGFR-2 antibody, or merestinib, an oral MET inhibitor, to gem/cis and biomarker on selected metastatic biliary cancer. Dr. Bergsland: Finally, Australian researchers reported results from the Christoral NET study. Adding chemotherapy to lutetium-177 dotatate in mid-gut neuroendocrine tumors added toxicity without improving efficacy. The results of these studies highlight the ongoing need to identify validated biomarkers that facilitate drug development. This trend is reflected in our clinical trials, with biomarker selected patient populations using tumor-based biomarkers, germline alterations, or circulating tumor DNA increasingly under study. Dr. Bergsland: Adaptive platform trial designs, such as the platform study of maintenance therapy in gastroesophageal cancer and PanCAN's Precision Promise clinical trial in the first line and second line treatment of metastatic pancreatic cancer, are being incorporated to more efficiently test new therapies by requiring fewer patients to understand if a potential therapy is working and support the testing of multiple investigational therapy simultaneously. ASCO Daily News: To take things one step farther, how are we doing in terms of actually delivering personalized cancer care? Are we making improvements in patient access to treatment and follow-up? Dr. Bergsland: The available data suggests we have a long way to go in terms of ensuring equitable access to care across all patients. Disparities in health care delivery were highlighted in several presentations. An analysis of NCDB data revealed that young adults with colorectal cancer in the lowest income and education population had worse overall survival. And regardless of income, patients in metropolitan areas have a lower risk of death, presumably due to greater access to care. Another group analyzed health care in Canada and determined that 1/3 of patients with non-curative gastroesophageal cancer never see a medical oncologist, and only 1/3 of patients receive chemotherapy. Dr. Bergsland: Care delivery and overall survival showed high geographic variability, with location of residents influencing access to care and overall survival and inferior outcomes for those living further from a cancer center. Dr. Yousef Zafar gave a keynote lecture focused on how advances in precision oncology can be realized equitably across all patient populations, communities, and health care systems. He reminded us that in 2017, only 60% of patients with metastatic colorectal cancer were getting appropriate molecular testing. He also reviewed the costs of cancer care and the impact financial toxicity has on patients. Dr. Bergsland: Dr. Zafar outlined a need for what he calls "precision delivery of care," which, to be successful, will require collaboration between drug manufacturers, insurance providers, health care providers, and patients, and discussions of clinical benefit toxicity and cost. In the era of precision oncology, novel methods for assessing the value of new drugs are needed, as our reimbursement models that incorporate cost effectiveness. Dr. Zafar stressed that all stakeholders will need to collaborate to find solutions that ensure precision delivery of molecular and immunotherapies to all patients. ASCO Daily News: Did we learn anything new or unexpected about the pathobiology of GI malignancies at this year's meeting? Dr. Bergsland: I think one of the most interesting sessions at the meeting was a keynote lecture given by Susan Bullman, a scientist at the Fred Hutchinson Cancer Research Institute. Dr. Bowman reviewed the importance of a microbiome in the human body and in disease. She explained that the naturally occurring microbes in our bodies may confer susceptibility to certain cancers, promote cancer progression, and modulate response to therapeutics. Dr. Bergsland: For example, tumor associated bacteria are metabolically active and can potentially increase or decrease the activity of certain chemotherapeutic agents, such as gemcitabine. In addition, there is a growing body of evidence that tumor microbiome may modulate the response to immunotherapy. Dr. Bullman's presentation highlighted this exciting new area of study as well as the many unanswered questions in the field, including whether the tumor microbiome itself might be a valid target for cancer therapy. Studies of the microbiome in colon cancer and other diseases are ongoing. ASCO Daily News: I agree, that was a very fascinating keynote lecture. Given the legalization of marijuana in an increasing number of states, an entire session at the symposium was dedicated to symptom management in the era of legalized marijuana and the opioid crisis. What notable points came out of that session? Dr. Bergsland: There is great interest in the use of cannabinoids in the face of increased access and legalization in a number of states in the US. The data suggests that patients prefer information about safety and efficacy from their health care providers, but many providers cite inadequate training in this area. Our understanding of the role of these agents is limited by a lack of prospective clinical trials. The strongest evidence for efficacy is in the area of the control of chemotherapy-induced nausea, but it's unclear if cannabinoids impact tumor growth, as most of the studies in this area have been preclinical. Dr. Bergsland: In terms of practical treatment considerations in the absence of high quality data on strain, dosing, ratios, and potencies of active ingredients and modes of use, a harm reduction model of care is recommended starting with very low doses, with THC-CBD combinations preferred over THC only preparations. Definitive recommendations are further complicated by the lack of information about drug-drug interactions and limited information about quality control. Overall, the panel felt that cannabinoids were not likely to ever replace opioids, so prescribers still need to know how to use opioids in the clinic, keeping an eye out for patients with risk for abuse of these agents and remembering to incorporate a bowel regimen as well as an antiemetic in the first few days. ASCO Daily News: This was truly an excellent recap. I think we can summarize by saying there was a wealth of research that was presented at the GI Cancer Symposium this year, both positive and negative, that's moving the field forward. It's been a pleasure speaking with you, Dr. Bergsland. Thank you for your time and your insight. To our listeners, thank you for tuning into the ASCO Daily News Podcast. If you are enjoying the content, we encourage you to rate us and review us on Apple Podcast. [MUSIC PLAYING] The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     [MUSIC PLAYING]  

Prof. dr. Egbert Smit, hoogleraar longziekten verbonden aan het Antoni van Leeuwenhoek, Amsterdam, vat de belangrijkste presentaties tijdens de ASCO 2019 samen op het gebied van longkanker. Hierbij bespreekt hij onder andere studies naar het gebruik van neoadjuvante immunotherapie en studies die gelijktijdig de VGEF- en EGFR-pathway blokkeren. Ook wijst hij op enkele nieuwe moleculaire doelwitten voor de behandeling van longkanker. Prof. dr. Anne-Marie Dingemans, longarts en hoogleraar longziekten aan Maastricht UMC+, presenteerde tijdens ASCO 2019 de opzet van de NVALT-22-studie. Dit is een prospectieve fase 3-studie die bij KRAS-gemuteerde, chemotherapienaïeve patiënten met niet-kleincellig longcarcinoom de effectiviteit zal vergelijken van chemotherapie met cisplatine plus pemetrexed versus chemotherapie met carboplatin, paclitaxel plus bevacizumab. De studie borduurt voort op de retrospectieve bevinding dat chemotherapie met carboplatin, paclitaxel plus bevacizumab bij patiënten met een KRAS-mutatie leidt tot een betere overleving dan andere vormen van chemotherapie. De studie loopt inmiddels in 25 ziekenhuizen in Nederland en heeft 170 van de beoogde 240 patiënten geïncludeerd. Prof. dr. Martin Reck, hoofd van de afdeling Thoracic Oncology bij de Lung Clinic Grosshansdorf in Duitsland, geeft commentaar bij de RELAY-studie, waarvan prof. dr. Kazuhiko Nakagawa tijdens ASCO 2019 de resultaten presenteerde. Deze studie evalueerde de effectiviteit en veiligheid van dubbele blokkade van de EGFR- en VEGFR-pathways in de eerste lijn bij patiënten met EGFR-gemuteerd, gemetastaseerd niet-kleincellig longcarcinoom (mNSCLC). Combinatie van ramucirumab met erlotinib resulteerde in een significante verbetering van de progressievrije overleving (HR 0,59). De toxiciteit kwam overeen met die van de individuele middelen. Nagakawa concludeerde dat deze combinatie een nieuwe behandeloptie vormt voor de eerstelijnsbehandeling van patiënten met EGFR-gemuteerd mNSCLC.  

Key Takeaways from the ASCO-SITC Clinical Immuno-Oncology with Dr. Steven Eric Finkelstein. Welcome to the "ASCO Daily News podcast." I'm Lauren Davis and joining me today is the "Immuno-oncology Daily News" Associate Editor, Dr. Steven Eric Finkelstein with Florida Cancer Affiliates the US Oncology Network. Dr. Finkelstein, welcome to the podcast. Thank you so much for having me. The Immuno-oncology Symposium just concluded on Sunday. How was this event compared to last year's? Well, this year's event was, again, extremely exciting. This year's event featured research and discussion surrounding themes of patient-centered rational steps to move the field of immuno-oncology towards the future. Now, as many of us know, immuno-oncology has dramatically altered the treatment landscape for many malignancies, and this progress has been extremely rapid over the last decade. As the field has progressed, researchers and clinicians are pushing it towards a better understanding of how immunotherapy can affect patients and the best and most rational combination approaches can improve responses and long-term outcomes. What presentations stood out to you? Another exciting area of research was that the combination of lenvatinib and pembro yielded promising antitumor activity and progression-free survival in patients with metastatic urothelial carcinoma. In abstract 11, a Phase Ib/II study was reported. And as we know, urothelial cancer can account for 90% of all bladder cancers. Pembro monotherapy is currently approved as a first-line therapy in patients who are ineligible to receive cisplatin or platinum-based chemotherapy. It's also approved as a second-line treatment for patients with advanced or metastatic urothelial cancer. Lenvatinib, a multikinase inhibitor, a VEGFR-1 through 3, FGFR-1 through 4, PDGFR-alpha, RET, and KIT is used as a single agent in several malignancies, including thyroid cancer and hepatocellular cancer. Dr. Vogelzang, who presented the results of the study, discussed the Phase II portion of the study, which included 20 patients with histologically confirmed metastatic urothelial carcinoma. The primary outcome in the trial was immune-related resist objective response at 24 weeks. Five patients achieved such a response for an overall response rate at 24 weeks of 25%. Dr. Vogelzang's conclusion was that lenvatinib plus pembro demonstrated promising antitumor activity with manageable adverse events. The response rate warranted further investigation and lenvatinib plus pembro combination will be studied in a Phase III trial in urothelial carcinoma. What other research were you interested in? A Phase Ia/Ib trial was launched in order to evaluate the safety of LY3321367, an anti-T cell immunoglobulin-domain and mucin-domain containing molecule 3, or TIM-3 antibody. Administered alone or in combination to LY3300054, which is an antiprogrammed death ligand, or PD-L1 antibody in patients with advanced, relapsed, or refractory solid tumors. An analysis of the trial that was presented by Harding at the meeting in Abstract 12. This focused on the safety, efficacy, pharmacokinetics, and pharmodynamic results seen with these treatment regimens. The key points are as follows-- treatment-related adverse reactions were mild, i.e. Grade two or less, in both treatment groups except for one patient with a Grade three anemia in Arm B. No dose-limiting toxicities, dose-limiting equivalent toxicities, treatment-related serious adverse events, or death was observed in either treatment arm. Approximately 68% in Arm A and 88% in Arm B of patients were positive for treatment emergent antidrug antibodies related to the LY3321367. Despite antidrug antibodies, there was no effect on pharmacokinetics noted That's great. Were there any education sessions that caught your attention? I think at the 2019 ASCO SITC Clinical Immuno-Oncology Symposium, what really struck me were the keynote addresses. On March 2, the keynote lecture from Dr. Rafi Ahmed of Emory University examined the basic scientific underpinnings of the field and focused deeply on T cell exhaustion and differentiation. In a second keynote address, Dr. Jedd Wolchok, of Memorial Sloan Kettering, took a broader look of the future of immunotherapy. And his main thesis was there was a need for a more rational approach to combination therapies. Indeed, it is apparent that the combination of therapies will be an important role for our future. That's wonderful. Were there any other takeaways that were important during the symposium? ASCO and the Society of Immunotherapy of Cancer, SITC, have really focused on developing recommendations for clinical trial reporting. Indeed, we need trial reporting that addresses the unique efficacy, toxicity, combination, and sequencing aspects of immuno-oncology treatments. As many know, ASCO and SITC had convened a working group that consisted of medical oncologists, immunologists, clinical research, biostatisticians, and representatives from industry and government to develop important recommendations, also known as Trial Reporting in Immuno-oncology, or TRIO recommendations. The recommendations based on expert consensus are important given that existing data to support evidence-based recommendations are limited. The recommendations given by TRIO are intended to improve the reporting of IO clinical trials and thus, provide more complete evidence on the relative benefits and risks of immuno-oncology. Given the rapid expansion of the number of IO clinical trials and ongoing improvements to evidence base using IO treatments and clinical care, it is apparent that these recommendations will likely need regular revision. And the annual meeting of ASCO and SITC will be an important place for TRIO recommendations to continually be updated. Thank you. Again, today, my guest has been Dr. Steven Eric Finkelstein. Thank you so much for being on our podcast today. It's been an absolute pleasure. Thank you so much. And to our listeners, thank you for tuning into the "ASCO Daily News" podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple Podcast.

Dr Choueiri presents, at a press conference at ESMO 2016, results of the CABOSUN comparitive trial, which assessed outcomes of patients with metastatic rencal cell carcinoma receiving cabozantinib versus sunitnib. Both drugs are tyrosine kinase inhibitors (TKIs) targeting VEGFR, however cabozantinib has additional actions in inhibition of MET and AXL. He describes the results, which demonstrate improved progression free survival in the cabozantinib arm, and considers its progression towards wider adoption and approval.

In this Toxicologic Pathology podcast, Stacey L. Fossey interviews author Peter Hall on his article "Femoral Head Growth Plate Dysplasia and Fracture in Juvenile Rabbits Induced by Off-target Antiangiogenic Treatment." Epiphyseal growth plate dysplasia (chondrodysplasia) might be considered as the pathognomonic feature of antiangiogenic treatment in preclinical species as it is reliably and dose-responsively induced in rodents and monkeys with vascular endothelial growth factor receptor (VEGFR) inhibitors, fibroblast growth factor (FGF) receptor inhibitors, matrix metalloproteinase inhibitors, and vascular targeting agents. The article suggests that the high prevalence of growth plate fracture in the rabbit may represent a potential additional adverse risk to those already established for children treated with antiangiogenic therapy.

Dr Incio speaks with ecancertv at EACR 2016 about obesity-associated inflammation that drives cancer. He considers the influence of age and obesity, with patients weight across all stages of life being linked to risks of cancer, and goes on to introduce ongoing studies into adipose tissues in breast cancer. For more from Dr Incio on pathways in pancreatic cancer, you can read about VEGFR here and IL-1ß/AT1 here.

Dr. Heather Wakelee of Stanford University Medical Center discusses whether or not cabozantinib - a drug already approved for thyroid cancer - can help patients with lung cancer. February 2014.

Dr. Heather Wakelee of Stanford University Medical Center discusses whether or not cabozantinib - a drug already approved for thyroid cancer - can help patients with lung cancer. February 2014.

Dr. Heather Wakelee of Stanford University Medical Center discusses whether or not cabozantinib - a drug already approved for thyroid cancer - can help patients with lung cancer. February 2014.

Dr. Nate Pennell from Cleveland Clinic reviews the LUME Lung-1 trial presented by Reck at ASCO 2013, of Taxotere with or without nindetanib (BIBF-1120), an anti-angiogenic multikinase inhibitor, in advanced NSCLC.

Dr. Nate Pennell from Cleveland Clinic reviews the LUME Lung-1 trial presented by Reck at ASCO 2013, of Taxotere with or without nindetanib (BIBF-1120), an anti-angiogenic multikinase inhibitor, in advanced NSCLC.

Dr. Nate Pennell from Cleveland Clinic reviews the LUME Lung-1 trial presented by Reck at ASCO 2013, of Taxotere with or without nindetanib (BIBF-1120), an anti-angiogenic multikinase inhibitor, in advanced NSCLC.

Analysis of VEGF signaling identifies potential therapeutic strategies for treating pathological angiogenesis.

Background: Everolimus is approved for treatment of anti-vascularendothelial growth factor (VEGF)-refractory patients with metastaticrenal cell carcinoma (mRCC). Clinical trials rarely mirror treatmentreality. Thus, a broader evaluation of everolimus is valuable forroutine use. Patients and Methods: A German multicenternon-interventional study documented mRCC patients starting everolimusafter failure of initial VEGF-targeted therapy. Primary endpoint waseffectiveness, defined as time to progression (TIP) according toinvestigator assessment (time from first dose to progression). Results:Of 382 documented patients, 196 were included in this interim analysis.

This is a commentary on the role of MET in cancer using Choueri et al as an example of rationale therapeutics and translational research.

Sandro De Falco, Angiogenesis LAB, Institute of Genetics and Biophysics “A. Buzzati Traverso", CNR, Naples, ITALY speaks on "PlGF/VEGFR-1 axis in pathological angiogenesis: hypoxic modulation and specific inhibition". This seminar has been recorded by ICGEB Trieste

The molecular mechanisms that regulate the earliest steps of lymphatic vascular system development are unknown. To identify regulators of lymphatic competence and commitment, we used an in vitro vascular assay with mouse embryonic stem cell-derived embryoid bodies (EBs). We found that incubation with retinoic acid (RA) and, more potently, with RA in combination with cAMP, induced the expression of the lymphatic competence marker LYVE-1 in the vascular structures of the EBs. This effect was dependent on RA receptor (RAR)-alpha and protein kinase A signaling. RA-cAMP incubation also promoted the development of CD31+/LYVE-1+/Prox1+ cell clusters. In situ studies revealed that RAR-alpha is expressed by endothelial cells of the cardinal vein in ED 9.5-11.5 mouse embryos. Timed exposure of mouse and Xenopus embryos to excess of RA upregulated LYVE-1 and VEGFR-3 on embryonic veins and increased formation of Prox1-positive lymphatic progenitors. These findings indicate that RA signaling mediates the earliest steps of lymphatic vasculature development. Copyright (C) 2010 S. Karger AG, Basel

Current Developments and Perspectives in Targeted Therapies Many different approaches for improving the prognosis of patients with advanced non-small-cell lung cancer (NSCLC) are currently being investigated. This article discusses the significance of maintenance therapy after primary chemotherapy and reviews study data on second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), inhibitors of insulin-like growth factor receptors (IGFR), vascular-disrupting agents (VDAs) and multi-TKIs of vascular endothelial growth factor receptors (VEGFR). The article also looks at the future prospects of using genetic markers in the field of NSCLC.

Das Glioblastoma multiforme (GBM, WHO-Grad IV) ist ein äußerst aggressiver und stark vaskularisierter Tumor. Trotz multimodaler Therapiekonzepte mit chirurgischer Resektion, Bestrahlung und Chemotherapie haben die betroffenen Patienten eine schlechte Prognose von lediglich 9 bis 15 Monaten Überlebenszeit nach Diagnosestellung. Innovative Therapiekonzepte sind daher dringend erforderlich. Im Fokus dieser Arbeit stand das abnorme Gefäßsystem maligner Hirntumoren. Aufbauend auf einem besseren Verständnis der Gefäßbiologie dieser Tumoren wurden potenzielle Strategien für Diagnostik und Therapie entwickelt und evaluiert. Progenitorzellen aus dem Knochenmark sind in vielfacher Weise an der Neoangiogenese von Tumorgefäßen beteiligt. Immundefizienten Ratten wurden in dieser Arbeit primäre humane MSC systemisch appliziert, nachdem den Tieren zuvor ein humanes Gliom implantiert worden war. Die Rekrutierung der MSC in den Tumor wurde immunhistochemisch nachgewiesen. Die endotheliale Differenzierung der MSC konnte mit gentechnisch modifizierten MSC-Linien bestätigt werden. Diese Zellen enthielten einen Vektor mit dem Reportergen RFP (red fluorescent protein), dessen Expression unter der Kontrolle des endothelspezifischen Tie2-Promotor/Enhancer-Konstruktes steht. Darauf aufbauend wurde eine MSC-Linie etabliert, bei der statt des Reportergens RFP das Selbstmordgen HSV-TK unter der Kontrolle des Tie2-Promoters steht. Die Hypothese hierzu ist, dass nach systemischer Verabreichung dieser MSC durch Zugabe von Ganciclovir eine selektive Toxizität auf den Tumor bewirkt wird. Zur genaueren Charakterisierung der Gefäßstrukturen in Hirntumoren wurde die Expression Lymphgefäß-assoziierter Moleküle in Gewebe unterschiedlicher Gliome untersucht. Die lymphangiogenen Wachstumsfaktoren VEGF-C,-D und ihr Rezeptor VEGFR-3 zeigten im GBM hohe Expressionswerte. Die Expression von VEGFR-3 unterschied sich signifikant von der in niedriggradigen Astrozytomen (WHO-Grad II). Podoplanin war in allen Gewebeproben des GBM sehr hoch exprimiert, in einigen Zellen zeigte sich eine Co-Lokalisation mit Prox-1. Die Expression war allerdings nicht gefäßassoziiert, sondern ausschließlich auf den Tumorzellen zu finden. Eine streng endotheliale Lokalisation zeigte sich dagegen im anaplastischen Oligodendrogliom (WHO-Grad III), in dem Podoplanin mit VEGFR-3 co-exprimiert ist. Durchgehend negativ für Podoplanin waren alle untersuchten Astrozytome (WHO-Grad II). Für weiterführende Untersuchungen zur Funktion von Podoplanin wurden zwei GBM-Zelllinien etabliert, die einen Podoplanin-Überexpressionsvektor stabil exprimieren. Die Ergebnisse dieser Arbeit unterstreichen die zentrale Bedeutung des Gefäßsystems für das GBM. Es wurde gezeigt, dass MSC effektiv aus der Peripherie in den Hirntumor rekrutiert werden und dort aktiv an der Angiogenese beteiligt sind. MSC eignen sich somit, nach genetischer Modifikation, als Vehikel für therapeutisch wirksame Gene, mit denen das neu entstehende Gefäßsystem des GBM gezielt angegriffen werden kann. Für die entsprechenden in vivo-Versuche wurde bereits eine gentechnisch modifizierte MSC-Linie entwickelt und ein Therapieschema entworfen. Obwohl das Gehirn unter normalen Bedingungen kein Lymphgefäßsystem besitzt, wurden im Gewebe der malignen Hirntumoren in dieser Arbeit auch Lymphgefäß-assoziierte Moleküle nachgewiesen. Die Expression des Rezeptor-Liganden-Systems VEGFR-3/ VEGF-C,-D korreliert dabei mit dem Malignitätsgrad der Hirntumoren. Das gegensätzliche Expressionsmuster von Podoplanin könnte ein diagnostisches Kriterium darstellen, um Hirntumore mit unterschiedlichem Malignitätsgrad histopathologisch voneinander zu unterscheiden oder es könnte eine potenzielle Zielstruktur für neue Therapieansätze darstellen. Mit den etablierten GBM-Zelllinien steht ein Zellmodell zur weiteren Analyse der noch ungeklärten Funktion des Podoplanins im GBM zur Verfügung.

The aim of the study was to further investigate the importance of local other and to detect possible differences of expression and localisation in poly- and monoovulatory species. Therefore ovaries of sexually mature gilts were collected at the local abattoir and follicles, which were determined to be in the follicular phase of oestrous cycle, ovarian stromal tissue and corpus luteum (CL) were prepared. In two experiments mRNA expression of gonadotropin receptors (LHR, FSHRregulatory factors during the final follicle growth in pig, to clarify relations among each), Aromatase (P450 Aro) and growth factors (fibroblast growth factor (FGF-1, FGF-2, FGF-7) and their receptors (FGFR-1IIIc, FGFR-2IIIb, FGFR-2IIIc), vascular endothelial growth factor (VEGF) and receptors (VEGFR-1, VEGFR-2), angiopoietin-tie-system (Angp-1, Angp-2, Tie-1, Tie-2) and nitric-oxid-synthase (eNOS, iNOS) were measured by qRT-PCR. An immunohistochemically determination and localisation was carried out for FGF-2, VEGF and VEGFR-1. Molecular size of FGF-2 was determined by westernblot. mRNA expression of the selected factors in pig total follicles and expression intensity in comparison to stromal tissue and CL was checked in experiment 1. Experiment 2 was concerned with the exact regulation of growth factors in the follicle compartments granulosa cells (GC) and theca interna (TI) during final follicular growth. A classification of follicles was performed according to follicular fluid oestradiol-17β (E2)-, progesterone and prostaglandin F2α content into four groups (2-3mm, 4-6mm, >7mm, post LH). Expression of FSHR decreased during follicle growth, while LHR and Aromatase increased. mRNA of FGF-family members was strongly expressed in stromal tissue. This was confirmed immunohistochemically by dominant localisation of FGF-2 protein in stromal cells. 18kDa and 22kDa isoforms of FGF-2 were overriding determined in stromal tissue. VEGF was located in GC and TI but not in stromal tissue. The receptor, VEGFR-1 was found in the endothelial- and smooth muscle cells of blood vessels. VEGF mRNA expression decreased after LH-peak. VEGFR-2 was upregulated in large follicles, VEGFR-1 after LH-peak. Angp-2/Angp-1 ratio was highest in small follicles, lowest in large follicles. After LH-peak the ratio rose again. Expression of eNOS was opposite with iNOS, which was downregulated in large follicles. FSH plays an important part in recruiting a folliclepool at time of luteolysis, while the further developing follicles become LH dependent. The number of LHR is an important selection criteria for the follicles. LH and E2 cause GC proliferation by mediators like FGF-7 and enhance angiogenesis by stimulating VEGF. While the follicle growth-up fast the pressure of oxygen in the follicular antrum decreases, whereby angiogenetic factors like VEGF and angiopoietins get stimulated and provide an adequate blood supply for the follicles. Activated by LH and VEGF eNOS is producing NO, which controls E2 synthesis and leads to a better blood flow in the TI through vasodilatation. Increasing E2 concentrations in large follicles stimulate Angp-1, which stabilise the now sufficient bloodvessel network in the TI. After the LH-peak Angp-2 destabilises the blood vessels, which is important for the process of ovulation and the succeeding angiogenesis in CL buildup. For follicle selection an important parameter seems to be the localisation of VEGF and FGF in the follicle. VEGF acts in the follicle and therefore follicles which express more VEGF and receptors have a developmental advantage. In cows this fact is suggested as one basic in selection of the one dominant follicle. FGF-2 in the pig is mainly expressed in stromal tissue and able to activate FGFR in the TI and increases angogenesis in a synergistic way with VEGF and its receptors. FGF-2 in stromal tissue consequently has influence on a few follicles and is maybe an important component in selection of follicles during final follicular growth in polyovulatory species.

The role of members of the Vascular Endothelial Growth Factor (VEGF) family and their receptors in angiogenesis, progression and pathophysiology of pituitary tumours is still poorly understood. In the present work, the expression and localization of the angiogenic factor VEGF-A and the lymphangiogenic factor VEGF-C, as well as VEGF receptors (VEGFR-1, VEGFR-2, VEGFR-3 and neuropilin-1), have been studied in normal and tumoural pituitary tissue and in transformed pituitary tumour cell lines. In addition, the role and mechanism of action of VEGFR-1 ligands have been investigated in normal and transformed rat pituitary cells. Immunohistochemical investigations in 3 normal human adenohypophyses showed that VEGFR-2 and neuropilin-1 were localized in blood vessel endothelial cells, while VEGFR-1 was found in endocrine cells. VEGF-A significantly induced ACTH and prolactin secretion in normal rat pituitary cell cultures, indicating a role of VEGF-A and VEGFR-1 in the regulation of the secretion of these pituitary hormones. In contrast, VEGFR-2 and its co-receptor neuropilin-1 may be needed to maintain optimal intrapituitary vascularization and blood vessel permeability. Although no lymphatic vessels were identified in normal adenohypophysis, the lymphangiogenic factor VEGF-C and its receptor VEGFR-3 were detected by immunohistochemistry, suggesting the involvement of the VEGF-C/VEGFR-3 system, usually implicated in lymphangiogenesis, in the maintenance of blood vessel permeability. The expression of VEGFR-1, VEGFR-2 and neuropilin-1 in a series of 39 pituitary adenomas reflected the same immunohistochemical localization pattern as observed in the normal adenohypophysis tissue. It was highly heterogeneous and mostly no significant correlation with different parameters, such as: tumour type, tumour grade, proliferation index (PI) and blood vessel number, was noticed. Only the absence of VEGFR-2 and neuropilin-1 correlated with a low PI, suggesting a role of these two receptors in increasing vessel permeability and consequently the availability of nutrients and oxygen for tumour cells. Functional studies, with the VEGFR-1-positive somatotrophinoma rat pituitary cell line MtT-S, showed that VEGF-A and the VEGFR-1 specific ligand PlGF, significantly stimulated the cell proliferation, through the activation of PI3K pathway and the induction of the anti-apoptotic factor Bcl-2 and the cell cycle promoter cyclin D1. VEGF-C immunostaining was detected in endocrine tumour cells of 10 adenomas and VEGFR-3 immunopositive vessels were found in 22 tumours, even if only 9 of them were positive for both VEGFR-3 and LYVE-1 (specific lymphatic vessel marker), suggesting that the VEGF-C/VEGFR-3 system may have a role in the regulation of tumour angiogenesis of pituitary adenomas, rather than in lymphangiogenesis, as already shown in other tumour types. In conclusion, the results of the present study provide strong evidence that VEGF may not only have a role in regulating pituitary adenoma neovascularization but also, through VEGFR-1, may affect pituitary adenoma pathophysiology by modulating growth, cell cycle progression and survival of the adenoma cells.

Zielsetzung dieser Arbeit war es, die Bedeutung der Expression von Liganden wie Vaskular Endothelial Growth Factor (VEGF) und Stem Cell Factor (SCF), sowie deren Rezeptortyrosinkinasen VEGFR-1, VEGFR-2 und Stem Cell Factor Receptor KIT für die Pathogenese der akuten myeloischen Leukämie (AML) genauer zu untersuchen. In neun von zehn der untersuchten leukämischen Zelllinien konnte eine starke VEGF Expression gezeigt werden, wohingegen die VEGFR-1 und VEGFR-2 Expression auf sechs bzw. zwei Zelllinien beschränkt blieb. Um der Überexpression von Rezeptortyrosinkinasen in den untersuchten Leukämiezelllinien eine pathogenetische Relevanz zuweisen zu können, wurde mit Hilfe der spezifischen Proteintyrosinkinaseinhibitoren SU5614, STI571 und SU1498 versucht, das Wachstum dieser leukämischen Zelllinien zu hemmen. Dabei zeigte sich, dass nicht die Expression von VEGFR-2 sondern nur die Überexpression und Stimulation von KIT eine proliferative Wirkung auf die untersuchten AML Zelllinien hat. Zur Bestätigung dieser Ergebnisse wurden zusätzlich verschiedene Apoptoseassays durchgeführt, die zeigen konnten, dass durch den Einsatz des PTK-Inhibitors SU5614 darüber hinaus Apoptose induziert werden kann. Auch die biochemischen Phosphorylierungsuntersuchungen des KIT Rezeptors in Kasumi-1 und KIT Rezeptor transfizierten HEK-293 Zellen belegten eindeutig eine Hemmung der Tyrosinphosphorylierung des KIT Rezeptors durch SU5614 Inkubation und bestätigen die Bedeutung des SCF/KIT Signalweges für das Zellwachstum von KIT positiven AML Zellen.