Podcasts about mdm2

Featuring a slide presentation and related discussion from Dr Raajit K Rampal, including the following topics: Overview of the current JAK inhibitor landscape (0:00) Factors predicting clinical benefit in patients with myelofibrosis (MF) receiving ruxolitinib (3:02) Clinical data supporting the use of fedratinib after prior ruxolitinib for MF (9:17) Emerging clinical findings on pelabresib in combination with ruxolitinib for previously untreated MF (12:13) Available clinical data with novel BET inhibitors (15:00) Utility of selinexor in combination with ruxolitinib for MF previously treated with ruxolitinib (16:50) Emerging efficacy and safety findings reported with imetelstat for MF (18:57) Clinical findings reported with the MDM2 inhibitor navtemadlin for MF (21:15) Available clinical data with the TGF-beta inhibitor elritercept for MF (24:05) Other novel agents and strategies under investigation for MF (26:06) CME information and select publications

Featuring an interview with Dr Raajit K Rampal, including the following topics: Clinical decision-making in the initiation and stopping of systemic therapy for myelofibrosis (MF) (0:00) Novel research strategies involving CDK4/6 inhibitors for MF (8:03) Implications of the JUMP study for clinical practice (10:00) Therapeutic switching strategies with JAK inhibitors for MF (12:17) Clinical rationale for the use of luspatercept and elritercept for MF (15:35) Emerging clinical data involving BET inhibitors for MF (16:57) Tolerability concerns with selinexor in patients with MF (20:01) Mechanism of and clinical data with the MDM2 inhibitor navtemadlin for MF (22:32) Additional novel strategies under clinical investigation for MF (25:52) Potential transformation of myeloproliferative neoplasms to acute myeloid leukemia (29:40) Management of polycythemia vera and essential thrombocythemia (34:27) General management principles for myeloproliferative neoplasms (37:53) CME information and select publications

Gain valuable insights into the complexities of diagnosing and managing dedifferentiated liposarcoma (DDLPS) and earn free CME credit with our latest podcast. This episode features expert guidance from Dr. Richard F. Riedel of Duke University and Dr. Candace L. Haddox of Dana-Farber Cancer Institute. Delve into the latest on identifying MDM2 and CDK4 amplification, challenges in diagnosing DDLPS, and updates on emerging therapies like CDK4/6 inhibitors and immunotherapies. Learn how a multidisciplinary approach enhances patient outcomes in this rare and aggressive soft tissue sarcoma. Listen now and advance your expertise! Click here to claim your CME credit: i3health.com/course-information/podcast-ddlps

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/CC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/ADF865. CME/CC/NCPD/CPE/AAPA/IPCE credit will be available until November 10, 2025.Building the Alliance in Dedifferentiated Liposarcoma: Integrating Personalized, Multidisciplinary Care With Innovative MDM2 Antagonists in Advanced Disease In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Sarcoma Alliance for Research through Collaboration. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent medical educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/CC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/ADF865. CME/CC/NCPD/CPE/AAPA/IPCE credit will be available until November 10, 2025.Building the Alliance in Dedifferentiated Liposarcoma: Integrating Personalized, Multidisciplinary Care With Innovative MDM2 Antagonists in Advanced Disease In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Sarcoma Alliance for Research through Collaboration. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent medical educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/CC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/ADF865. CME/CC/NCPD/CPE/AAPA/IPCE credit will be available until November 10, 2025.Building the Alliance in Dedifferentiated Liposarcoma: Integrating Personalized, Multidisciplinary Care With Innovative MDM2 Antagonists in Advanced Disease In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Sarcoma Alliance for Research through Collaboration. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent medical educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/CC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/ADF865. CME/CC/NCPD/CPE/AAPA/IPCE credit will be available until November 10, 2025.Building the Alliance in Dedifferentiated Liposarcoma: Integrating Personalized, Multidisciplinary Care With Innovative MDM2 Antagonists in Advanced Disease In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Sarcoma Alliance for Research through Collaboration. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent medical educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/CC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/ADF865. CME/CC/NCPD/CPE/AAPA/IPCE credit will be available until November 10, 2025.Building the Alliance in Dedifferentiated Liposarcoma: Integrating Personalized, Multidisciplinary Care With Innovative MDM2 Antagonists in Advanced Disease In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Sarcoma Alliance for Research through Collaboration. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent medical educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/CC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at PeerView.com/ADF865. CME/CC/NCPD/CPE/AAPA/IPCE credit will be available until November 10, 2025.Building the Alliance in Dedifferentiated Liposarcoma: Integrating Personalized, Multidisciplinary Care With Innovative MDM2 Antagonists in Advanced Disease In support of improving patient care, this activity has been planned and implemented by PVI, PeerView Institute for Medical Education, and Sarcoma Alliance for Research through Collaboration. PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent medical educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.Disclosure information is available at the beginning of the video presentation.

Featuring perspectives from Dr Mrinal Gounder, including the following topics: Epidemiology, classification, genetics and diagnosis of sarcomas (0:00) Contemporary medical treatment of sarcomas (5:29) Targeted therapy for the treatment of sarcomas (9:01) Incidence, pathophysiology, classifications and clinical manifestations of liposarcomas (16:27) Current clinical treatment of dedifferentiated liposarcomas (23:14) Targeting the MDM2-p53 pathway for dedifferentiated liposarcomas (28:20) Available data with MDM2 inhibitors for dedifferentiated liposarcomas (36:37) Emerging research and future directions for dedifferentiated liposarcomas; clinical treatment landscape of desmoid tumors (1:01:22) CME information and select publications

El Dr. Rogelio Trejo Rosales, oncólogo médico, especialista en el Centro Oncológico Personalizado (COPE) de la Ciudad de México, México, nos comenta sobre lo más destacado en tumores del sistema nervioso central, presentado en el Congreso de ASCO 2024, resaltando los siguientes estudios: Abstract 2004: resultados de supervivencia del estudio que evaluó el uso de PCV (procarbazina, CCNU y vincristina) en primera línea frente a temozolomida, ambos en combinación con radioterapia, para pacientes con oligodendroglioma de grado 3 con mutación IDH y codeleción 1p/19q. Los objetivos fueron evaluar la supervivencia global (SG) y supervivencia libre de progresión. GBM AGILE: estudio fase II/III diseñado para evaluar múltiples terapias para el glioblastoma recién diagnosticado y recurrente de manera eficiente y adaptativa. El objetivo primario fue mejorar la SG. Abstract 2071: estudio fase 0/I que se centró en la evaluación de brigimadlin para el tratamiento del glioblastoma multiforme (GBM) con amplificación de MDM2. El objetivo fue desarrollar un modelo de farmacocinética, farmacodinámica y eficacia para brigimadlin utilizando xenoinjertos derivados de pacientes con GBM. Este modelo se utilizará para informar sobre el desarrollo clínico del medicamento en combinación con radioterapia en GBM recién diagnosticado y no metilado en MGMT. Fecha de grabación: 11 de junio 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.

The profound impact of the COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been felt across various domains, including the realm of cancer research and treatment. As scientists delve deeper into the intricate mechanisms of this viral pathogen, intriguing revelations have emerged regarding its potential influence on cellular processes pivotal to cancer development and progression. In a new study, researchers Wafik S. El-Deiry and Shengliang Zhang from Brown University and Lifespan Health System shed light on the intricate interplay between the SARS-CoV-2 spike protein and the tumor suppressor p53, a key guardian of genomic integrity. On May 3, 2024, they published their new research paper in Oncotarget's Volume 15, entitled, “Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.” In this study, researchers El-Deiry and Zhang uncovered a hitherto unknown facet of the SARS-CoV-2 spike protein's impact on cancer cells. Their findings, meticulously detailed in their research paper, have ignited a newfound curiosity within the scientific community. Full blog - https://www.oncotarget.org/2024/05/09/sars-cov-2-spike-protein-disrupts-p53-tumor-suppressor-pathway/ Paper DOI - https://doi.org/10.18632/oncotarget.28582 Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28582 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, SARS-COV2 spike, p53, MDM2, chemotherapy 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: 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/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

BUFFALO, NY- May 6, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 3, 2024, entitled, “Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.” Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. In this new study, researchers Shengliang Zhang and Wafik S. El-Deiry from Brown University and Lifespan Health System examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. “We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells.” The researchers further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike were found to have increased cell viability as compared to control cells. Further observations on γ-H2AX expression in spike-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics. More efforts should be directed at studying the effects of the SARS-CoV-2 spike and other viral proteins on host DNA damage sensing, response and repair mechanisms. “A goal would be to understand the structural basis for maximal anti-viral immunity while minimizing suppression of host defenses including the p53 DNA damage response and tumor suppression pathway. Such directions are relevant and important including not only in the context of viral infection and mRNA vaccines in general but also for patients with cancer who may be receiving cytotoxic or other cancer treatments.” DOI - https://doi.org/10.18632/oncotarget.28582 Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28582 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ 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: 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@IMPACTJOURNALS.COM

In this episode of SurgOnc Today®, Brian E. Kadera, MD, Ben Hinrichs, MD, and Konstantinos Chouliaras, MD, focus on the diagnosis and work-up of fatty tumors in the extremity and the retroperitoneum. They highlight the imaging features, the utility of biopsy and specifically, MDM2 fluorescence in-situ hybridization. They also review the pitfalls of gross and microscopic margin assessment.

Giovanni tem um diagnóstico de vitiligo e recebe constantemente conselhos diversos nas ruas para tratar o seu quadro; Maria Alice, a avó do Porchat, acreditou que a lama do Mar Morto pudesse curar uma micose no seu dedão. A doutora Aline Bressan, especialista em dermatologia, elucida as principais crenças infundadas sobre os quadros que afetam a nossa pele. Confira o terceiro episódio da nossa "Edição especial sobre fake news em saúde". Referências: 1. Antoniou C, Schulpis H, Michas T, Katsambas A, Frajis N, Tsagaraki S, Stratigos J. Vitiligo therapy with oral and topical phenylalanine with UVA exposure. Int J Dermatol. 1989 Oct;28(8):545-7. doi: 10.1111/j.1365-4362.1989.tb04613.x. PMID: 2583897. 2. Sociedade Brasileira de Dermatologia. Vitiligo. Disponível em: Vitiligo - SBD. Acessado em: 30/11/2023 3. Hospital Israelita Albert Einstein: Vida Saudável. Vitiligo: o que é, quais são as causas e como identificá-lo?. Disponível em: Vitiligo: o que é, quais são as causas e como identificá-lo? | Vida Saudável | Conteúdos produzidos pelo Hospital Israelita Albert Einstein. Acessado em: 30/11/2023 4. Ministério da Saúde. Portadores de Vitiligo podem desenvolver sintomas emocionais em decorrência da doença, alerta especialista da Rede Ebserh. Disponível em: Portadores de Vitiligo podem desenvolver sintomas emocionais em decorrência da doença, alerta especialista da Rede Ebserh — Empresa Brasileira de Serviços Hospitalares (www.gov.br). Acessado em: 30/11/2023 5. Bakry OA, Hammam MA, Wahed MM. Immunohistochemical detection of P53 and Mdm2 in vitiligo. Indian Dermatol Online J. 2012 Sep;3(3):171-6. doi: 10.4103/2229-5178.101812. PMID: 23189248; PMCID: PMC3505423. 6. Sociedade Brasileira de Dermatologia. Micose. Disponível em: Micose - SBD. Acessado em: 30/11/2023 7. Ministério da Saúde. Micoses endêmicas. Disponível em: Micoses Endêmicas — Ministério da Saúde (www.gov.br). Acessado em: 30/11/2023. PP-CMR-BRA-0662

Brain cancer linked to nuclear pore alterations  Transcript of this podcastHello and welcome to the NanoLSI podcast. Thank you for joining us today. In this episode we feature the latest research by Masaharu Hazawa and Richard Wong at the Kanazawa University NanoLSI, alongside Mitsutoshi Nakada and colleagues at Kanazawa University.The research described in this podcast was published in Cell Reports in August 2023 Kanazawa University NanoLSI websitehttps://nanolsi.kanazawa-u.ac.jp/en/Brain cancer linked to nuclear pore alterations Researchers at Kanazawa University report in Cell Reports how alterations in nuclear pores lead to the degradation of anti-tumor proteins. Several types of cancer are believed to be linked to alterations of macromolecular structures known as nuclear pore complexes.  These structures are embedded in the nuclear envelope, a membrane barrier that separates the nucleus of a cell from the cytoplasm (the liquid filling the rest of the cell).  They consist of proteins called nucleoporins, which regulate the transport of molecules across the nuclear envelope, including enzymes that enable the synthesis of DNA.  Whether nuclear pore complex alterations play a role in glioblastoma, the most common type of cancer originating in the brain, is unclear at the moment.  Now, Masaharu Hazawa, Mitsutoshi Nakada and Richard Wong from Kanazawa University and colleagues have found a link between the functioning of nuclear pore complexes and glioblastoma — specifically, they demonstrated the inactivation of a tumor-suppressing protein called p53. The protein p53 is crucial in cancer prevention.  The corresponding gene TP53 encodes proteins that prevent mutations of the genome and is the most frequently mutated gene in human cancers.  Gaining insights into how p53 inactivation happens is crucial for understanding tumorigenesis in general and glioblastoma in particular.So how did the researchers go about it?Mitsutoshi Nakada and Richard Wong and colleagues first checked whether any nuclear pore complex proteins were amplified (that is ‘overexpressed') in glioblastoma.  They found that one such protein, called NUP107, showed overexpression.  Further investigations revealed that NUP107 is a potential oncoprotein in glioblastoma; its overexpression degrades the function of the cancer-suppressing p53 protein.  They also found that MDM2, another protein, is overexpressed simultaneously with NUP107.  MDM2 is also known to mediate p53 protein degradation. Further studies will be necessary to uncover the full molecular pathways at play, but the scientists speculate that the increased amount of NUP107 proteins in the nuclear pore complexes of glioblastoma cells results in nuclear pore complex structures that regulate the transport of molecules from the nucleus to the cytoplasm in a way that promotes p53 degradation.  This scenario is referred to as nuclear transport surveillance.  Experiments in which NUP107 proteins were depleted re-activated p53, consistent with NUP107 providing the structural stability of glioblastoma NPCs. The findings of Mitsutoshi Nakada and Richard Wong and colleagues confirm that alterations of nuclear pore complexes contribute to the pathogenesis of glioblastoma.  As Mitsutoshi Nakada and Richard Wong put it : “Together, our findings establish roles of nuclear pore complexes in transport surveillance and provide insights into p53 inactivation in glioblastoma.”  ReferenceDini Kurnia Ikliptikawati, Nozomi Hirai, Kei Makiyama, Hemragul Sabit, Masashi Kinoshita, Koki Matsumoto, Keesiang Lim, Makiko Meguro-Horike, Shin-ichi Horike, Masaharu Hazawa, Mitsutoshi Nakada, and Richard&NanoLSI Podcast website

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.27.538576v1?rss=1 Authors: Morral, C., Ayyaz, A., Kuo, H.-C., Fink, M., Verginadis, I., Daniel, A. R., Burner, D. N., Driver, L. M., Satow, S., Hasapis, S., Ghinnagow, R., Luo, L., Ma, Y., Attardi, L. D., Koumenis, C., Minn, A. J., Wrana, J. L., Lee, C.-L., Kirsch, D. G. Abstract: Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced GI injury. Through single-cell RNA-sequencing of the irradiated mouse intestine, we find that p53 target genes are specifically enriched in stem cells of the regenerating epithelium, including revival stem cells that promote animal survival after GI damage. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce revival stem cells. Using intestinal organoids, we show that transient p53 expression is required for the induction of revival stem cells that is controlled by an Mdm2-mediated negative feedback loop. These results suggest that p53 suppresses severe radiation-indued GI injury by promoting intestinal epithelial cell reprogramming. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Description: In which Sophia speaks with Carol Prives, the Da Costa Professor of Cell and Molecular Biology at Columbia University and a member of both the National Academy of Sciences and the American Academy of Arts and Sciences, about her journey researching the structure and function of the p53 tumor suppressor protein. She delves into the importance and regulation of p53, including its relationship with kinases, Mdm2, and the Mevalonate pathway. Editorial Note: During the discussion regarding the mevalonate pathway, the listener should note that genes in this pathway had reduced expression when mutant p53 levels were reduced. Pathway genes, themselves, were not mutated.

A new review paper was published in Oncotarget's Volume 14 on March 11, 2023, entitled, “Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells.” Cancer therapy is limited by toxicity in normal cells and drug-resistance in cancer cells. In his latest review, Mikhail V. Blagosklonny, M.D., Ph.D., from Roswell Park Comprehensive Cancer Center discusses the theory that cancer resistance to certain therapies can be exploited for protection of normal cells—simultaneously enabling the selective killing of resistant cancer cells by using antagonistic drug combinations, which include cytotoxic and protective drugs. “No cancer cell, no matter how resistant it is, can survive chemotherapy in a cell culture. In the organism, however, therapy of cancer is limited by killing or damaging normal cells. Selective protection of normal cells from chemotherapy would increase the therapeutic window, improving the therapeutic outcome. Needless to say, reduction of side effects and better quality of life are very important for a cancer patient.” Depending on the mechanisms of drug-resistance in cancer cells, the protection of normal cells can be achieved with inhibitors of CDK4/6, caspases, Mdm2, mTOR, and mitogenic kinases. When normal cells are protected, the selectivity and potency of multi-drug combinations can be further enhanced by adding synergistic drugs, in theory, eliminating the deadliest cancer clones with minimal side effects. “I also discuss how the recent success of Trilaciclib may foster similar approaches into clinical practice, how to mitigate systemic side effects of chemotherapy in patients with brain tumors and how to ensure that protective drugs would only protect normal cells (not cancer cells) in a particular patient.” Read the full review: DOI: https://doi.org/10.18632/oncotarget.28382 Correspondence to: Mikhail V. Blagosklonny - Blagosklonny@oncotarget.com, Blagosklonny@rapalogs.com Keywords: oncology, resistance, cyclotherapy, trilaciclib, rapamycin 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 Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.17.528998v1?rss=1 Authors: Scholz, N., Siebzehnrubl, F. A., Licchesi, J. D. F. Abstract: Programmed cell death is a complex and tightly regulated sequence of events that determines cell fate during tissue homeostasis, development, and pathogenesis. The small protein modifier ubiquitin mediates important regulatory functions during cell death by regulating the stability and activity of checkpoint proteins and the assembly of cell death signalling complexes. The caspase family of cysteine aspartases are essential effectors of apoptotic cell death. Components of the ubiquitin system including RING ubiquitin ligases XIAP, MDM2, RBX1; RBR E3 ubiquitin ligases Parkin and LUBAC; and HECT E3 ubiquitin ligases NEDD4 and Itch are also substrates of caspase-mediated cleavage. In the case of NEDD4 and Itch, the single cleavage event occurs outside of the catalytic HECT domain and it remains unclear whether such cleavage events impact on ubiquitin ligase activity and/or function. Here, we identified the E3 ubiquitin ligase HECTD1 as the third HECT E3 cleaved by caspase-mediated cleavage during apoptotic cell death, in a manner which does not affect the integrity of the catalytic C-ter HECT domain. We mapped the single cleavage event to DFLD1664{downarrow}S and showed that the cleaved C-ter product, which contains the HECT ligase domain, is as stable as the endogenous full length protein. We also found that HECTD1 transient depletion led to reduced caspase-3 activity, but not caspase 8 nor 9. Furthermore, we also identified caspase-3 as the protease responsible for HECTD1 cleavage at Asp1664 suggesting that HECTD1 and caspase-3 might be part of a novel feedback loop mechanism during apoptotic cell death. This study highlight novel crosstalk between cell death mechanisms and the ubiquitin system and raises important questions on whether proteolytic cleavage of E3 ubiquitin ligases might represent an underappreciated mode of regulation during cell death mechanisms. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

MDM2 is a key regulator of p53, the protein responsible for tumor suppression and apoptosis — an intractable, yet undruggable target. Previous attempts to drug MDM2 have been met with significant toxicities issues. The MDM2 oral inhibitor milademetan has the potential to address these issues and in doing so may open the door to treating multiple tumor types, as identified by standard molecular testing. Indeed, studies with milademetan have demonstrated promising preliminary results in liposarcoma. Let the Wall Street veteran, CEO Avanish Vellanki, walk you through the RAIN.

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh's Hillman Cancer Center, highlight key advances in early phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting and also address toxicities, including immune checkpoint inhibitor-associated myocarditis. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. My name is Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology, specializing in melanoma and phase 1 therapeutics at the University of Pittsburgh's Hillman Cancer Center. I am the guest host of today's podcast. My guest today is Dr. Jason Luke, a colleague and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center here.  Today, we'll be discussing advances in early-phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting.   You'll find our full disclosures in the show notes, and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Thanks so much for the invitation. It was a great ASCO, and I hope everyone had a good time.  Dr. Diwakar Davar: So, onto our abstracts. So, the first one that we'll be discussing, and Jason as you know we've done this before. We'll be rapidly transitioning between phase 1 therapeutics, melanoma, and advanced phase 2 and 3 trials, but you know this is something you do very well. So Abstract 2504, it's a phase 1 trial of TIM-3 inhibitor cobomilab immunotherapy and in combination with PD-1 inhibitors nivolumab and dostarlimab. The AMBER Trial that was presented recently, and in full disclosure, both you and I actually are on this abstract. So, what do you think of this abstract? What do you think of the data that is discussed, and how do we contextualize this in relation to what needs to be done in this space?  Dr. Jason Luke: So, I think this is an exciting abstract because it brings forward what may be the next high-priority immune checkpoint to try to target in clinical oncology. To level-set, I think everybody listening will know about PD-1 and CTLA-4 as immune checkpoints. In the last year, we've had LAG-3 come forward as now a standard of care element of armamentarium in melanoma, and we look forward to further studies of LAG-3 and other tumor types as we think it should be a good partner where PD-1 is otherwise approved.  So here now, we hear about TIM-3, which is another negative regulatory checkpoint on a number of different immune subsets. And in this abstract, the antibody targeting TIM-3 was cobolimab. So, TIM-3 is a very interesting molecule. It has, what you might call, pleiotropic effects in the immune system. So, while in the context of this abstract, it was being targeted as another immune checkpoint on T cells, it's important to point out that TIM-3 has other regulatory roles in other immune subsets such as myeloid cells and very particularly dendritic cells, and that's important because it might bring in another element of the innate immune system to try to drive anti-tumor responses. So, it's an exciting target because it might be able to expand the groups of patients who could benefit from immune checkpoint blockade.  So, in this abstract, we see initially the phase 1 data of combining cobolimab, anti-TIM-3 with anti-PD-1 of a couple of different flavors. And what you could take from this abstract is that in the phase 1 setting, the drug was well-tolerated and combined well, and had pharmacokinetic properties that would be consistent with what we'd expect for this kind of a monoclonal antibody. I think we have to marry this abstract, which is really the phase 1 data about safety in pharmacokinetic (PK) to another abstract presented in the melanoma session, which showed an expansion cohort of patients who got cobolimab plus nivolumab or dostarlimab.  And there we did see a 50% response rate, albeit that there was heterogeneity of patients being treatment naïve versus treatment-experienced. So, what I would say to this on a high level is that I think these data are preliminarily exciting, suggesting that further investigation into TIM-3 may be valuable in terms of expanding the population of patients initially in melanoma, but there will data coming soon in lung cancer and in other tumor types with another novel checkpoint. And I think if we think ahead into the future, the question is probably going to end up being, which combinations of checkpoints for which patients. That's pretty exciting to think about. We've seen a lot of data of PD-1 plus other molecules, and I think some future biomarker stratification really will be necessary to know which patient would benefit the most from which of these combos, but for the time being, this is exciting data to see where the field is going to go over the next couple of years.  Dr. Diwakar Davar: Great. And I guess, to your point, one important thing to highlight from the abstract is your point about the role of the different compartments. There was actually a very interesting dose-response relationship with the highest dose of the drug not necessarily being the most effective dose, suggesting that yes, as you escalate, you may have different effects in different compartments, and maybe therefore a broad selection of doses might be required to ensure that you have optimal engagement of the optimal target.  So, the next abstract is Abstract 3007. This is the tumor-agnostic efficacy and safety of erdafitinib. So, we now know that FGFR pathway aberrations are found from 77% of all malignancies, FGFR targets are now U.S. Food and Drug Administration (FDA) approved in cholangiocarcinoma with pemigatinib, infigratinib, and as well with erdafitinib metastatic urothelial cancer. We know that these agents are not necessarily effective tests in 1 tumor type because these alterations have risen in multiple tumor types. So, the RAGNAR trial, looking at this across multiple tumor types, what do you make of the interim analysis result presented by Dr. Loriot?  Dr. Jason Luke: So, I'd say that this is probably the future of targeted therapy. And so, I think that where we have activity in 1 disease, it's very likely we would have activity in others. So, the author has described this as the largest basket trial of a molecularly defined subset that's been pursued to date. There are upwards of more than 200 patients in the study. I think it's really important, as we think about the data, to realize, though, that all FGFR alterations are not exactly the same thing. And so, in this study, they gave erdafitinib to patients with solid tumors of any FGFR altered status. And so that's FGFR1, 2, 3, 4 mutations or gene fusions. And that's a lot of heterogeneity in there actually.  And in this study, there were two-thirds fusions and one-third mutations, mostly in FGFR2 and 3. That will become relevant as we start to think about the results. On a high level, I have to say that it is impressive in pan-cancer fashion, just selecting by FGFR alteration, there's about a 30% response rate observed. I think that no matter what, that's going to be valuable considering these were patients with refractory tumors with 3 lines of prior therapy on median. I think what we need to know more is the breakdown of which specific molecular alteration and FGFR in which tumor types drove most of the benefit.  So, for example, in bladder cancer where erdafitinib is already approved, that's almost entirely an FGFR3 fusion setting. So we know the drug is effective there. And so I think there will be a further breakdown of the data. As it matures more, you really start to tease out, is it really the case that any FGFR alteration can be treated or there are some that really ought to be the high priorities that we really ought to be going after. I think it would be remiss not to also note, however, that while there's excitement about this sort of pan-cancer approach, the current generation of FGFR inhibitors are not exactly the easiest drugs to take.  And so, the in-class, hypophosphatemia and stomatitis really does lead to dose reductions in a lot of the patients. And I think that that's probably really important to emphasize is that despite the pan-tumor activity, there's still a lot of potential in this field to refine further because it's almost certainly the case that if we had less off-target toxicity, so to say, we could improve the efficacy beyond that 30% that we saw here.  All the same, I think this is exciting for the concept of a pan-cancer tumor agnostic sort of approach, and we'll really look forward to more data to come from this study over the next, hopefully, few months.  Dr. Diwakar Davar: And I guess 1 corollary to that is that we now need to start looking for FGFR alterations in multiple tumor types. So, tests, tests, tests. All right, Abstract 3004, phase 1a/1b dose escalation and expansion study of the MDM2-p53 antagonist BI 907828 in patients with multiple solid tumors including advanced, metastatic, liposarcoma. So, we've recently had data of the previously undruggable KRAS, and now we've got previously undruggable p53, for which we now have targets. So, Jason, what do you make of the p53 targeting approach, in this case, using MDM2 and this particular drug from Boehringer Ingelheim?  Dr. Jason Luke: So, I think that this is an exciting abstract exactly for the reason that you mentioned, which is that p53 has been, and unfortunately, to some degree, still remains, one of those holy grails but undruggable targets in oncology. So MDM2, for those who are listening but might not be aware, is a negative regulator of p53. So, the concept here then is if you drug it, you might release p53 to reactivate activity in that pathway, and then p53 being the guardian of the genome, so to say, potentially leading to apoptosis of cancer cells.  And so, this drug binds MDM2 and MDM2 can be amplified as a resistance mechanism in p53 and several tumor types. And so here, they showed data for the early part of a clinical trial investigating the small molecule, BI 907828, but then they focus specifically in liposarcoma, which is a disease known to be an MDM2 amplified. And so, the results were pretty interesting. The toxicity of this kind of an approach, just to note, is really in class. It leads to some gastrointestinal (GI) toxicities as well as hematologic problems, and this goes again for most regulators of the cell cycle will have these effects, whether they're CDK inhibitors or MDM2 or p53 modulators.  But I think what was very interesting, this is a disease liposarcoma where chemotherapy, functionally speaking, has no role. We, unfortunately, give it to some patients sometimes, but it has almost no activity, and they observe that in poorly differentiated liposarcomas, the response rate was about 12%, but the stable disease was quite durable. And so, I think that really is potentially a big deal because this is an orphan disease. It really lacks any other treatment. But as you zoom out from that, if you start to think about targeting amplified MDM2 in other settings, I think the activity that we see here is intriguing, and potentially suggests that we may be coming to a future where we'll have multiple, sort of, orthogonal approaches after reactivating p53. There were actually other abstracts at ASCO Annual Meeting of other molecules that were less mature also along this line.  So, I think, very exciting to take away from this, one, a potential treatment for liposarcoma for all of those patients that anybody listening actually sees, but secondarily this concept of targeting p53, which I think we'll see a lot more of over the next couple of years.  Dr. Diwakar Davar: Excellent. Moving on to the Abstract 3002, this is a phase 1, two-part multicenter, first-in-human study of DS-6000a of an antibody-drug conjugate comprising the anti-CDH6 IgG1 monoclonal antibody that is attached to a topoisomerase I inhibitor payload via a cleavable linker. And so basically, a way in which you can give topoisomerase: (1) TOP1 inhibitor, (2) CDH6-expressing cells. This was studied in advanced renal cell carcinoma (RCC) and advanced ovarian cancer in this abstract presented by Dr. Hamilton. Jason, what do you think of the results and what do you think of this approach in general, this antibody-drug conjugate (ADC) approach using novel targets as well as novel payloads?  Dr. Jason Luke: I think this is one of those that you can't help but be pretty excited about, and I think in the context of the data shown at the plenary session in breast cancer for antibody-drug conjugates (LBA3), I think this is really where the field is going to start to go. So, you mentioned that this is an antibody-drug conjugate that targets cadherin 6 or CDH6, which people will remember from biochemistry class and medical school, or something is a cell-cell adhesion molecule, really a basement membrane protein. So, the concept of targeting it really is just to go after a latch mechanism to get the molecule into the tumor where you want. And CDH expression is very high in renal cell carcinoma, upwards of 80% of samples, also high in ovarian cancer, which is why they chose those 2 tumors to go after.  So, the ADCC, and you described its structure just a little bit, but it's essentially the same backbone as trastuzumab deruxtecan, which we saw this outstanding activity for HER2 and breast cancer on the plenary, with these 8 chemotherapies moieties attached to it, but here now, targeting it instead to HER2, with this molecule now to CDH6. And I think, again, you can't help but be impressed. There were treatment responses on almost every dose level of the dose escalation in this study. There's in fact only 1 patient whose tumor was not, at least, stable disease or a PR, and I think that that just goes to show the power of truly bringing the chemotherapy in a targeted manner into the tumor microenvironment. Responses were heterogeneous. They were not super deep responses per se, but the stable disease was quite durable in the study, and the patients were going out more than 7 months. And again, realizing this is at the lower dose levels as we're increasing the dose and move this in their earlier lives of therapy is likely to be even more effective.  They did show a waterfall plot of the reduction in CA 125 for the patients with ovarian cancer that really looked quite impressive. And given that that's our clinical biomarker that we commonly follow, it may actually even more indicative of the benefit we would see as opposed to resist.  Now, again, there is some toxicity. It is a chemotherapy moiety that's conjugated to the ADCs. So, the most common toxicities were nausea, vomiting, and low platelet counts, but these are kind of toxicities that we're quite accustomed to with chemotherapy. Just to summarize, I think there's a lot of promise for this kind of antibody-drug conjugate targeting, and I think it can only be impressive that they had this amount of activity in the dose escalation of the study. [I] very much look forward to the expansion cohorts in renal and ovarian, which we'll presumably expect to see later this year, early in the next year.  Dr. Diwakar Davar: And as you alluded to, this really was parallel that ASCO, by the standing ovation given to Dr. Modi when she presented the DESTINY04 data of trastuzumab deruxtecan in HER2-low breast cancer, basically now redefining breast cancer from 4 camps, now we have to think of not just HER2 amplified or HER2-high, but also HER2-low. So yes, really have to now rethink how we classify these diseases (LBA3).  So Abstract 2509, the efficacy of anti-PD-1/PD-L1 immunotherapy in non–small cell lung cancer dependent based on CD8 and PD-L1 status. So really Dr. Galon taking us into what he has now described as the immunoscore—really a way of characterizing tumors. A way of thinking about tumors that you've also championed, Jason, in terms of this T cell-inflamed and uninflamed hypothesis. So, tell us a little bit about how these jives with your work and how you would think about lung cancer patients responding and not responding to immune checkpoint inhibitors (ICI) therapy in this context?  Dr. Jason Luke: Yeah. I think the focus quickly here on the immunoscore, so the people are aware of that, I think is really important for diving into these specific results. You have to realize our fundamental underlying predicate for immune checkpoint blockade inhibitor response is that patients have mounted an adaptive immune response. So, CD8 T-cells have gone into the tumor where they elaborate chemokines and cytokines like interferon gamma, which upregulates the expression of PD-L1 in the tumor but also in the surrounding immune cells.  So, you realize that even though antibodies are targeting PD-1, it's really that we're targeting that tumor microenvironment. So, the more robustly we can measure that, and we understand it, the more likely we are to know whether or not the patient is going to benefit. So, this is where the immunoscore comes in. The immunoscore is actually a fairly simple test. It's one slide, immunohistochemistry slide where they can stain jointly for CD8 and PD-L1 on the same slide. And that allows them to do a number of different things beyond just testing the total level of PD-L1. They can test the CD8 density, the PD-L1 expression, but then also the interaction between CD8 T-cells, their distance from each other, from PD-L1 expressing cells, and so on and so forth.  And so really [this] can give us a much more robust analysis of what all is going on in the tumor microenvironment again, off of a single slide. So here then, in this abstract, for patients with non–small cell lung cancer receiving anti-PD-1, they then compared the utility of only PD-L1 testing versus doing the immunoscore. And so, it was actually quite a large set. They had about 250 patients in their analytical set and then split about 150 or 180 or something into the training and validation sets, and they compared the immunoscore against 2 different standard PD-L1 antibodies, the 22C3 as well as the SP263. And what they saw was a high concordance for expression between PD-L1 and the immunoscore.  That's good, because, again, they're measuring PD-L1 in both of those. And so that was a good, sort of, level set. The immunoscore, however, allows them to look to 7 different parameters, again, beyond just PD-L1, as I mentioned. So, CD8 density, interaction, distance, and this kind of thing. Then in these test and training cohorts, they were able to actually split out patients who are PD-L1 positive into further groups, those that were immunoscore low and that were high. And in so doing, they were actually able to sort of dramatically predict the likely progression-free survival on PD-1 checkpoint blockade in those different non–small cell lung cancer groups.  So why is this important? Selection of patients by PD-1 has been very useful in the field of non–small cell lung cancer, but it's hardly a panacea. You're not at all assured your patient is going to do well just because they're PD-L1. And here comes a second assay that can be done in a standard of care setting. So, the immunoscore is a test. You could just order it, and that really does give you much more predictive power about who's likely to do well and who isn't. And I think this test and more broadly multi-spectral imaging is really going to become a core component to how we risk stratify and predict outcomes to checkpoint blockade and lung cancer, but broadly in other tumor types over the next couple of years.  Dr. Diwakar Davar: Okay. Now, moving on from a biomarker for PD-L1 and PD-1 to a setting in which PD-1 was just recently U.S. Food and Drug Administration (FDA)-approved, so I'll give a brief background to the trial that you've actually developed and led. And so, this is KEYNOTE-716, the abstract in question is LBA9500 (late-breaking abstract) 9500, but this is the distant metastasis-free survival (DMFS) data readout. The DMFS, distant metastasis-free survival with pembrolizumab versus placebo in the adjuvant setting for patients with stage IIB or IIC, that is high-risk node-negative melanoma and the data from the phase 3 KEYNOTE-716 study.  So, this data, at least the recurrence-free survival (RFS) data was actually earlier published, you had presented it earlier last year and also more recently this year, but it was published recently in Lancet. And we know that 716 is a study in which, for the first time ever, we have an immune checkpoint inhibitor PD-1 that was studied against placebo with the high-risk node-negative setting in stage IIB and C melanoma, demonstrated a significant RFS benefit in the setting against placebo. And now we have the DMFS readout.  Maybe you could tell us a little bit about both the RFS and the DMFS data, and why this is such an important advance for these patients.  Dr. Jason Luke: Thanks. And I agree this really is a sea change in how we thought about stratification of patients with melanoma, but I think this broadly has implications for other tumor types as well. So, in melanoma, we've historically thought of its involvement of the lymph nodes—stage III as being the high-risk disease, but we also, if you look at the outcomes from the AJCC, we see the patients with stage IIB and IIC, so deep primary lesions, actually have similar bad outcomes as those patients with stage IIIA and IIIB. And so anti-PD1 and adjuvant therapy and melanoma were originally proved for stage III, but having understood that about 5 years ago actually, started to think, well, why not also treat the patients with stage II if they're at similar risk.  And we pursued KEYNOTE-716 as you mentioned, and it read out last year as a positive trial for recurrence-free survival. And the abstract here then was to look at the impact on distant metastasis-free survival. So, while the regulatory consideration for approval, and it is approved and it's available for patients now, was based on relapse, what we really want to be preventing is the development of metastatic disease because presumably that would correlate with the eventual death of the patient from cancer.  So, in the abstract here, we see the first update for DMFS, which also was positive on its first analysis, the hazard ratio at 0.64. And so, again, very similar to the RFS benefit, showing about a 35-36% reduction in distant metastasis-free survival. And this is a theme that we've seen across adjuvant studies in melanoma, all the adjuvant studies in fact, is that the RFS improvement, the relapse-free survival hazard ratio mirrors very closely the distant metastasis-free survival ratio. We saw that again here. I think it just emphasizes that anti-PD-1 immunotherapy is highly effective in melanoma no matter what stage it's in, but rather related to the risk of death for melanoma.  And so this really has a practice changing in the field of melanoma oncology. Patients need to be referred to medical oncology early for discussion around risk stratification and consideration of adjuvant therapy—I think even at the same time that they're having resection of their primary lesion, and it even calls into  question of whether or not we should even fully be doing procedures like sentinel lymph node biopsies any longer, considering we can make the decision to give adjuvant therapy now based on the primary—albeit that's a controversial area of discussion.  And I would just love for this to start to penetrate into other disease settings. We've seen more recently, approval for neoadjuvant therapy in lung cancer and we see in kidney cancer, bladder cancer. We see adjuvant therapy in—I think we're going to see immunotherapy starting to become an important part of the armamentarium in these hard-to-treat cancers, even at the time that perioperatively before or after surgery.  So definitely a major change in the way we're thinking about stratifying patients and emphasizes that you need to get those patients with melanoma in to have that discussion around adjuvant therapy probably at the time of the primary lesion resection.  Dr. Diwakar Davar: And finally, Abstract 2507, single-cell profiling of human heart and blood in patients with checkpoint inhibitor-associated myocarditis. So, this is data from the NGH Group, Dr. Villani and colleagues are presented by Dr. Blum. We know that myocarditis is an uncommon but very serious immune related adverse event (irAE), and here in this particular dataset, this group which has done a lot of underlying work to really uncover the role of certain key phenotypes, cellular phenotypes, in the development of myocarditis it's presenting the data in the context of ICI-related myocarditis. So, what do you think of this data, what do you think of the use of checkpoint inhibitors are now, as you've said, migrated linear in the lifecycle of the patient, what do we need to be thinking about and how does this improve our understanding of both the use of the drug and what we need to be worried about?  Dr. Jason Luke: I think the toxicities of immunotherapy, while, less frequent than, say, chemotherapy, can actually be more disastrous. In the rare patients, we have extreme immune-related adverse events, there is an incidence of actually life-threatening and fatal events. And so, myocarditis, associated with checkpoint blockade, is one of those things that could be seen, and here at ASCO Annual Meeting, we saw a couple of abstracts summarizing the experience from the National Cancer Institute following myocarditis events, and then this abstract in a translational level trying to better understand what is actually going on in terms of the immune response in those myocarditis cases.  And so, I thought this was actually a very interesting abstract. There was only a small number of patients. They had 13 samples from patients who had had endomyocardial biopsies in the context of immune-related myocarditis, and you might say, well, only 13 samples, but fortunately, this is quite a rare event, less than 1% of patients who get immune checkpoint inhibitors. And what they saw was relatively unsurprising, which is that in patients who were having myocarditis, they saw an increase in T cells and in K-cells, as well as activated CD8 and CD4 T-cells.  I think what was very interesting was when they started to dig into what were the phenotypes of the cells and what were the pathways that were turned on. Again, it was not especially surprising to see that they saw increased levels of interferon signaling and immune-receptor signaling as well as motility and adhesion, but this really, I think emphasizes that there are potentially interventions beyond just the general immune-suppression approaches that we give. They could be more nuanced but perhaps more efficacious because sadly, patients do pass away when they develop this. And in their cohort of 13 patients, 3 of those patients died. And specifically, in looking in those 3 patients, they actually saw that all 3 patients had a shared T cell cluster. And they can't exactly say what it is exactly yet, but I think it's very interesting to see that because it suggests that there's probably something about the T cell response in those patients that disproportionately triggered a fatal event.  And if we can understand that better, we then may be able to really tailor our interventions in a way that is more useful. Because, frankly, the way these patients usually present is they show up in the emergency room (ER), and they're seen by an ER doctor who thinks they're having acute coronary. They ship them off to the catheterization (cath) lab. They open him up, and then they get in there, and there's nothing going on. There's no plaque. And so now, all of a sudden, everyone is quite confused. And so, if we had better ways to search for that ahead of time to be aware of it, we might have better interventions because usually what happens right at that moment is everybody gets very confused and starts calling the oncologist, and we start slapping on steroids and other immunomodulatory agents, but sometimes it's late.  So, I think this is a great abstract. It's really starting to preliminary give us an idea of what is the actual biology that underpins these terrible events, and we can hope that we can build off that over time hopefully to eventually come up with better predictors and then obviously better interventions to try to avoid these outcomes in a small but real number of patients.  Dr. Diwakar Davar: Excellent. One other point is you and I are both involved in drug development, and as we start thinking of side effects. Side effects are really on the flip side of responses in drug development. So really 1 point to make of this is that when people start developing side effects rather than, as you say, putting your hands up in the air and waving them around, 1 of the things that we should be doing in drug development is possibly biopsying these patients because we could get new PD insights into how these drugs work, why they work, and particularly which sub-populations themselves they work on, particularly in the early-drug development setting when you oftentimes don't have that many responses.  With that, thank you, Jason, for sharing your insights with us today.  Dr. Jason Luke: Thank you.  Dr. Diwakar Davar: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So, thank you for your attention, and we will sign out.      Disclosures:  Dr. Diwakar Davar:   Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences  Consulting or Advisory Role: Instil Bio, Vedanta Biosciences  Consulting or Advisory Role (Immediate family member): Shionogi  Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences  Research Funding (Inst.): Zucero Therapeutics  Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:   Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine  Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure  Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)  Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio  Disclaimer: 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.     

Zapraszamy na wykład Krystiana Latosa zorganizowany w ramach współpracy z Polskim Towarzystwem Astrobiologicznym AstroBio, maj 2022 r. Człowiek poszukując życia w kosmosie dokonuje jego eksploracji i potrzebne są mu do tego narzędzia. Jakie wyposażenie, jakie narzędzia powinny się znajdować w laboratorium poza naszą planetą? Ludzie przygotowują się do tego, żeby ponownie stanąć na powierzchni Księżyca (np. program Artemis). Jednym z najważniejszych celów misji jest ustanowienie placówki, która pozwoli na dłuższy pobyt na Księżycu. Założenie długoterminowej bazy księżycowej nadającej się do zamieszkania i wyposażonej w laboratorium mogłoby potencjalnie przynieść ogromne korzyści nauce, a także stać się poligonem testowym technologii, które będą wykorzystywane w misjach marsjańskich. Wykładowca opowiedział najpierw o badaniach materiałów nieożywionych, o początkach Księżyca, o geologii i geochemii Księżyca, o powstawaniu regolitów i kraterów uderzeniowych. Opowiedział też o regolicie jako dobrym źródle surowców - pierwiastków i związków chemicznych, które mogą być wykorzystane przez mieszkańców placówki. Następnie Krystian Latos opowiedział o badaniu życia i jego prekursorów w warunkach pozaziemskich. Mówił o badaniach księżycowych związków organicznych, o wyznaczeniu limitów dla życia poza Ziemią, i o poszukiwaniach życia pozaziemskiego. Wykład zakończył opowiadając o badaniach biologicznych w środowisku habitatu, w którym docelowo mają mieszkać ludzie. Wykładowca omówił bioregeneracyjne systemy podtrzymywania życia (BLSS), badania ewolucji mikrobiomu i sposobów jego ograniczania, a także zmiany fizjologiczne i psychologiczne zachodzące u ludzi po długoterminowym pobycie na Księżycu. Krystian Latos - doktorant na Wydziale Chemii Uniwersytetu Jagiellońskiego. Na tym samym wydziale ukończył studia magisterskie na kierunku Chemia medyczna. W czasie licencjatu, w Zespole Biologii Chemicznej i Projektowania Leków badał inhibitory interakcji MDM2/p53. W ramach pracy magisterskiej zajmował się chemią bioortogonalną – projektowaniem i syntezą heterodienów do reakcji hetero-Dielsa-Aldera z odwróconym zapotrzebowaniem elektronowym wykorzystywanych w obrazowaniu dystrybucji leków przeciwnowotworowych. Popularyzator nauki. Jego zainteresowania naukowe są związane z lekami przeciwnowotworowymi, chemią in vivo, czyli uczynieniem komórki organizmu kolbą reakcyjną i, naturalnie, astrobiologią. Prywatnie zapalony czytelnik i pasjonat wszystkiego co tajemnicze i niezbadane. Wykład przygotowany we współpracy z Polskim Towarzystwem Astrobiologicznym https://astrobio.pl/ Znajdź nas: https://www.youtube.com/c/WszechnicaFWW/ https://www.facebook.com/WszechnicaFWW1/ https://anchor.fm/wszechnicaorgpl---historia https://anchor.fm/wszechnica-fww-nauka https://wszechnica.org.pl/

Avanish Vellanki, Cofounder and CEO at Rain Therapeutics, discusses the role of p53 and MDM2 in cancers like liposarcoma, the mechanism of action of milademetan, and the positive pre-clinical data presented at the 2021 World Conference of Lung Cancer. As Mr. Vellanki explains, p53 regulates the cell cycle and is essential for tumor suppression. MDM2 is a crucial regulator of p53. If MDM2 is overexpressed, p53 can be inactivated, leading to tumor growth and cancer progression. Milademetan, Rain Therapeutics' lead product candidate, inhibits MDM2, and, in doing so, is hypothesized to reactivate p53 and thus control cancer growth in approximately 50% of cancers without a p53 mutation. Mr. Vellanki notes that MDM2 inhibition has been studied for a number of years. However, in the past, blood toxicity has been an issue. One reason for that is previous treatment regimens would allow the drug to accumulate in the tissues of patients. Milademetan does not accumulate in tissues when patients take milademetan for 3 days and then no treatment for 11 days. This allows the drug to be effective but prevents blood toxicity. This dosing schedule, according to Mr. Vellanki, has led to triple-to-quadruple the length of progression free survival compared to standard of care in liposarcoma, milademetan's main indication. At the 2021 World Conference of Lung Cancer, pre-clinical data suggested milademetan could also be safe and effective in treating malignant pleural mesothelioma. To learn more about liposarcoma and other rare cancers, visit checkrare.com/diseases/cancers/

Dr. Jason Luke, director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center, discusses advances in immunotherapy across the spectrum of malignancies featured at the 2021 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Jason Luke, the director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center. Dr. Luke also serves as associate professor of medicine at the University of Pittsburgh School of Medicine. His clinical focus is on immunotherapy for advanced solid tumors, as well as cutaneous malignancies and melanoma. He joins me to discuss advances in immunotherapy featured at the 2021 ASCO Annual Meeting. Dr. Luke has relationships with most of the pharmaceutical companies that have funded the research discussed in this episode. His full disclosures are available on the transcript of this episode. Dr. Luke, always great to have you on the podcast. Dr. Jason Luke: Well, thanks so much for the invitation today. ASCO Daily News: Well, there was an abundance of novel therapies and practice-changing studies presented during this year's [ASCO] Annual Meeting. Did you detect any themes among all of the great studies presented during the meeting? Dr. Jason Luke: Well, I agree. And as I was sort of taking the fire-hose of abstracts in this year, I thought there were four themes that really seemed to stand out to me. And when I was thinking through them, I think the first one was the validation of a new checkpoint, or a third validated checkpoint for use in clinical practice. A second one was really the emergence of immunotherapy, now being used in the curative setting, meaning either in adjuvant studies or in neoadjuvant studies. And the third area was advancements in this management of metastatic disease with practice-changing trials. And then the fourth area, which is always near and dear to me, is novel therapeutics with the development of the next generation of immunotherapies, and those early data that might give us a hint towards what might be coming next. ASCO Daily News: OK, so let's first look at the third validated checkpoint for use in clinical practice. That's Abstract 9503. Dr. Jason Luke: Yeah, absolutely. So this year at ASCO, we saw the results of a clinical trial described as the RELATIVITY-047 study, which was a global randomized double blind phase II/III study comparing anti-PD-1 antibody with nivolumab (nivo) versus a combination of nivolumab with the anti-LAG-3 antibody relatlimab. And so LAG-3 is a molecule that many will be familiar with, but perhaps not everyone. And LAG-3 is another receptor on T cells that can become up-regulated as T cells become dysfunctional in the tumor microenvironment. And so all are aware of the concept that infiltrating lymphocytes can get into tumors, and then they get blocked by these immune checkpoints. And so LAG-3 is another immune checkpoint expressed on these tumor infiltrating lymphocytes. And I don't have time to go into all of this, but in the preclinical space, blocking LAG-3 with an antibody is actually, in many mouse models, more effective than blocking a PD-1 or PD-L1. And so there's been a lot of interest. LAG-3 was one of the first targets to really develop as a co-target to PD-1. And just to zoom forward then to the clinical trial, this was a study where patients with advanced, untreated, metastatic melanoma were randomized one to one to either get relatlimab plus nivolumab, in what they are describing as a fixed dose combination, meaning that there's an infusion of the dose once a month, relatlimab 160 milligrams plus nivolumab 480 milligrams. And that was the same dose. And so it's only one infusion, even though it's two drugs, one infusion. That was compared with nivolumab. And there were a number of stratification factors, et cetera, in the study. And they're useful to get into the minutia, but right now, I think not so important. This, like I said, was a gated study, meaning they did a phase II trial first, to try to prove that there was a benefit in a smaller sample of patients. And if they hit the endpoint, they then went on to a phase III trial. And that's exactly what happened. So in this trial, progression-free survival (PFS) was the primary endpoint. And, interestingly, it was evaluated by blinded independent central radiology. And that may sound like a mouthful, but we'll come back to why that's important a little bit later. And there was a hierarchical testing strategy, such that the PFS had to be established first, before the investigators can look at overall survival and overall response rate. But given that background, there really was a quite substantial and clinically impressive difference between these two arms. And so we call relatlimab "rela" for short. So rela plus nivo demonstrated a substantial improvement, markedly statistically significant improvement, compared with nivolumab monotherapy, so that at 1 year, at 12 months, the progression-free survival for the combination arm was 47.7%, compared to 36% for nivolumab. And the median PFS was 10.1 months for the combination versus 4.6 months from nivolumab. So you can see that's more than a doubling of progression-free survival, with a hazard ratio at 0.75 and a p value at 0.006 or 0.0055. So why does that matter? Well, we have thought for a long time in the field about combination immunotherapy, and people think of PD-1 and CTLA-4 combination. And these data, when compared sort of across trial comparison, which is always a little dangerous, but they look very similar to what we saw with nivolumab plus ipilimumab (ipi), in terms of the absolute improvement in the benefit in terms of median progression-free survival, between relatlimab plus nivo, as compared with ipi plus nivo in the CheckMate-067 study. And I mentioned this blinded independent central radiology, that complicates things a little bit, because the landmark comparisons between having the radiologist evaluate the scans and having the investigators evaluate the scans, actually gives a little bit of variation in terms of the outcomes. But if you just compare them on a high level, they actually look very similar. And along those lines, the really important thing is that relatlimab plus nivolumab is much better tolerated with much less side effects than nivolumab plus ipilimumab. So, in fact, in this clinical trial, we see that the rates of grade 3-4 adverse events are on the order of what we saw with nivolumab monotherapy in CheckMate-067. Now, interestingly, in this study, RELATIVITY-047, the rates of grade 3 adverse events for nivolumab monotherapy were actually about half of what they had been seen in the previous phase III trial. And I think that that just suggests that all of us, as a field, are getting better at managing these immune therapy toxicities. One other piece of information that was very interesting to look at was when the outcomes were broken down by subgroups, particularly the biomarkers of PD-L1 positivity, and LAG-3 positivity. These biomarkers actually did not inform the outcomes, in which case, I mean, that nivolumab plus relatlimab was actually effective across all the subgroups. And so one might have hypothesized, going into this, that patients with high LAG-3 would do better with a LAG-3 treatment. That was not what was seen. In fact, all patients benefited with the combination. And that's relevant to clinical practice, because, as we think about applying this treatment, I do not think we're going to be able to use biomarkers, at least initially, to be able to differentiate who should get what. And rather this just suggests that basically all patients who are going to get PD-1 monotherapy would be better served by giving the combination. So I was the discussant actually for this abstract, and one of the questions I tried to get at was, well, does that mean that you would just essentially replace PD-1 monotherapy across the board in melanoma with this combination? And I think the answer is, not quite yet, but maybe someday. And what I mean by that, is that there are still some very high-risk patients that we treat. And particularly those are patients with high lactate dehydrogenase, brain metastases, rapid progression, et cetera. And those are the patients where, at least I, predominantly use nivolumab plus ipilimumab, or nivo plus ipi. And that's because nivo plus ipi is the treatment for which we have the best long-term data, and we know the most about it in terms of treating high risk patients. So I would continue to use that until this trial, at least. Is more mature, so that we can get data about the response rate, the overall survival, and so on and so forth. But I think there's really no question, looking at this relatlimab plus nivolumab data, that it does change the standard of care in melanoma, and that, for most patients, who would have gotten PD-1 monotherapy, they're now going to be directed towards this combination, given it's well tolerated and appears to be highly active. And I think, thinking beyond melanoma now, if this is now a second, a third checkpoint, but a second one we can combine with nivolumab with little toxicity, I think it opens up a huge new world of clinical investigation, possibly adding doublet checkpoint to chemotherapy. Basically everyone everywhere we've seen PD-1 combined with chemotherapy, and obviously that's quite exciting just thinking about improving outcomes. And we're going to discuss all the different ways that PD-1's been impacting the standard of care across different settings. ASCO Daily News: Excellent. Well, let's shift our focus now to the curative use of immunotherapy. Let's start in the adjuvant setting with the KEYNOTE-564 study. That's LBA 5. Dr. Jason Luke: So plenary presentation for the KEYNOTE-564 study, which was adjuvant pembrolizumab versus placebo in high-risk renal clear cell renal cell carcinoma. And so this is an important trial, because there have been decades, actually, of immunotherapy clinical trials in the adjuvant setting, which have not demonstrated a benefit. That also includes actually VEGF-TKIs, which also did not show a benefit. But in this large study, so almost 1,000 patients, 994 patients, they were randomized one to one to receive pembrolizumab or placebo. And the eligibility population were pathological T2 with intermediate and high risk features all the way through metastatic disease that's been fully resected. And the outcomes here, again, I think were very impressive. And so the disease-free survival was statistically significant, with a hazard ratio of 0.68. And what does that mean in reality? Well, the 2 year disease-free survival was 77.3% for the patients getting pembrolizumab compared to 68.1% for those getting the placebo. So you can see basically a 10% 2 year improvement in disease-free survival. And though the data were quite immature, the early analysis of overall survival also suggested a statistically significant benefit. So p value was 0.02 and hazard ratio was 0.54. Now we'll be very interested to see how that matures over time. But I think again these are practice-changing data, to suggest that, basically, all high-risk patients with clear cell renal cell cancer are now going to be receiving anti-PD-1 immunotherapy in the adjuvant setting. I think it does raise the question, and we'll discuss it now across other diseases as well, in terms of, are we over-treating patients. But this has been a constant struggle in medical oncology for many, many years. But it's very hard to see a treatment like this, with such a benefit, and not think that you want to give this basically to almost all the patients. But, hopefully, biomarkers to inform which patients benefit most will be coming over the relatively near future for renal cell. But I think those are becoming a little bit more obvious in some other diseases. ASCO Daily News: Looking at non--small cell lung cancer, Abstract 8500, that's the IMPOWER-10 trial, that caught a lot of attention. That was trending on Twitter for a while. What are your thoughts on that trial? Dr. Jason Luke: Yeah, absolutely, so the IMPOWER-010 or 010 study, this study looked at PD-L1 inhibition in the adjuvant setting, versus a placebo. So this was another very large trial where patients with early to later high-risk disease, so stage 1b to 3a, they received standard chemotherapy as adjuvant treatment, but then were randomly assigned to get PD-L1 versus best supportive care. And this was an interesting clinical trial, [ and] had a complicated statistical design where the first analysis was to look at the impact in PD-L1 positive patients. Secondarily, then, they looked at randomized patients. And then thirdly, they looked at intention-to-treat. And this was a positive study. So in the disease-free, in the PD-L1 high patient population, the disease-free survival did not reach the median, with a 2 year benefit at 74.6% versus 61%, so again a 13% improvement in 2 year disease-free survival. And that was highly statistically significant, hazard at 0.66. And, again, that's the PD-L1 high population. So, thinking about biomarkers then, it looks clear that the PD-L1 positive group is the one that disproportionately benefits, because as we went through the rest of the hierarchical testing, the disease-free survival in randomly assigned patients, and then in intention-to-treat patients, those numbers got a little less strong. And it really probably suggests that the PD-L1 positive group is the one that's going to drive almost all of the benefit. So it'll be interesting to see how this data matures, and how it's interpreted in the community. I mean, you mentioned the discussions on Twitter, which I sometimes participate in. And I'm going to come back to a little later how it's very interesting to see how thought leaders for various malignancies sort of take these data into consideration. I think clearly in GU cancers, when we talked about the KEYNOTE-564 pembrolizumab data, the sense was, this is an immediate change in the standard of care. When we look at this data for non--small cell lung cancer, however, the sense I've gotten from some investigators is, this is early data. And they really do want to see that overall survival before that's really going to have high uptake. But we'll have to kind of see how that goes. Maybe selecting for PD-L1 in that population would make that difference, to really let you feel confident. But it'll be interesting again, like I said, as more time passes and as we see more data, and as other PD-1, PD-L1 agents come into this same space, if there's reproducible data that will help them feel more confident. ASCO Daily News: Right, well, another trial that attracted a lot of attention was CheckMate-577. That's Abstract 4003. Do you think this trial will move the needle in esophageal or esophagogastric junction (GEJ) cancers? Dr. Jason Luke: So I think this is a real important trial, because we've historically thought of certain tumor types as immunotherapy sensitive versus not sensitive, melanoma, lung cancer, et cetera. And gastrointestinal (GI) tumors predominantly have fallen into that latter group, where we think where there isn't as much of a benefit. Obviously there are approvals for esophageal and gastric cancers, but I think this study really shows how we can move the needle in terms of maybe curing more patients. So CheckMate-577 looked at adjuvant nivolumab. And these were stage II and stage III patients with esophageal or GEJ, and they got neoadjuvant chemoradiation treatment and then surgery, all of that being standard of care, but then went on to get a randomization 2 to 1 to either nivolumab or placebo. And again, as you mentioned, this is an important trial. The disease-free survival (DFS) was statistically and substantially improved for the patients getting nivolumab versus placebo, after that definitive therapy. So in the group receiving nivolumab, the median disease-free survival was 22.4 months, compared to only 11 months in the patients getting the placebo. That was a hazard of 0.69 and a p value at 0.003. And, again, thinking about biomarkers here, there was a broad population of patients treated. But when you look at the breakdown of who benefited the most, the patients benefiting in this trial were almost entirely those patients who had a PD-L1 composite signature at greater than 5,  combined positive score (CPS) greater than 5. And so it's really the case that the PD-L1 positive patients with esophageal cancer seemed to benefit the most. And so I don't know how you think this doesn't impact the standard of care. In the total population there was a doubling of DFS, and in the PD-L1 high it was actually almost a tripling. And so I think, immediately, at least for PD-L1 high patients, they should go on to get adjuvant PD-1 after definitive chemotherapy, radiotherapy (RT), then surgery. And I think this is really exciting, when we think about, this is disease, obviously, it's very, very difficult to treat. And outcomes in metastatic disease are not what we want. And this really suggests we may be able to really benefit a lot of patients moving forward. ASCO Daily News: Excellent. So what are your takeaways from Abstract 9500, the KEYNOTE-054 trial of adjuvant pembrolizumab for melanoma? Dr. Jason Luke: Yeah. Thanks, so in melanoma we've had immunotherapy with checkpoint blockade now for a decade. And adjuvant clinical trials have been ongoing for most of that decade. And it's been standard of care to give our patients checkpoint blockade again for several years. I think what was really interesting about the update for KEYNOTE-054, which was the study of pembrolizumab (pembro)  versus placebo in stage III melanoma, was the authors on this update looked at the impact of crossover after initial progression. So in the clinical trial, patients were randomized one to one to either receive pembro or placebo. And at the time of progression, they could then cross over and get the other treatment, right? So this trial was the first trial to be designed to be able to ask that question, immunotherapy now versus immunotherapy later. And what we observed in this study was that the response rate to getting pembrolizumab in the metastatic setting, if you had gotten the placebo on the adjuvant trial, was approximately similar. It was right around 40% And that's actually what we saw on the KEYNOTE-006 study that got pembrolizumab registered. So that was really, really interesting. And it suggested that if patients progress in the adjuvant setting and get treatment with PD-1 in the frontline metastatic, and they're still in good shape, they actually can have similar outcomes than what we would have expected if they had not had that adjuvant experience. And so I think this is really important. It doesn't actually answer the question about overall survival, which is really what we want to know. Does adjuvant immunotherapy improve overall survival? But it does suggest that patients can have this benefit, even if they wait for treatment. One thing that was really interesting to see was that, for those patients who had pembrolizumab, in the adjuvant setting, and then had a progression event, who went on to get pembrolizumab again, actually had much lower outcomes. And so I think that that's something to be cautious about. I think if patients progress on adjuvant PD-1, the data from this trial really suggest that going back to PD-1, even if there's been a period of time, is not a real great idea. And many of us in the field have kind of advocated of going to CTLA-4 combination in those patients anyway. But I would think these data really do suggest that that's important. So broadly speaking, then, I think these data are important to suggest that if you wait to give immunotherapy, you can still get a good benefit, at least in melanoma. And what I thought was really interesting across all of these abstracts, so for kidney cancer, lung cancer, esophageal, melanoma, was we saw, I think, based on the investigator feedback, or the thought leaders in the field, was that disease-free survival or relapse-free survival was really interpreted somewhat differently in different settings. And so I think, in melanoma, I think we have for a long time thought that adjuvant therapy was important, despite the fact, we don't have overall survival for PD-1 antibodies. In the renal cell data, again, where immunotherapy has been a backbone, albeit with IL-2 and various different immunotherapies, again, a lot of enthusiasm. When we looked at lung cancer and esophageal cancer, where I think investigators are more used to biomarker selection, they were a little more nitpicky about which populations we should treat. And so I'm very interested to see how this entire field sort of develops, and how the thought leaders for each disease take these data in. But, if you take a step back, on a really high level, when we think about giving PD-1 checkpoint blockade, it's generally speaking a low-toxicity treatment. And there's a tremendous impact on recurrence and potentially cure in the adjuvant setting. And that is just so exciting when we think about truly making a difference on cancer. We're talking about people never having recurrence and never dying of metastatic disease. And if we think about the outliers among the thousands of patients that have these diseases, and just go out to 5 years, 10 years from now, that's going to be a lot of people alive because they got immunotherapy after surgery. ASCO Daily News: Well, that would be fantastic. Thanks, Dr. Luke, for your great analysis of the adjuvant setting. Let's focus now on the neoadjuvant setting. Abstract 8503, the CheckMate-816 trial, seems to be on everyone's radar. What can you tell us about it? Dr. Jason Luke: Absolutely, so I think we just got done talking about adjuvant therapy. But an alternative would be to say, is there a way that we can deliver this immunotherapy, perhaps to enhance the immunotherapy and either improve the surgery or actually maybe even avoid the surgery, moving into the future. And so that is a really exciting paradigm as well. And so the first of these was in non--small cell lung cancer, the CheckMate-816 study. And the initial results of this study were actually presented at AACR earlier this year, but now updated here at ASCO. And what we saw was that there was a major improvement, 10 times improvement, in pathologic complete response for giving nivolumab plus chemotherapy. I mean literally 2% pathologic complete response with chemotherapy, up to more than 20% with this combination with immunotherapy. And what the investigators updated here was a number of details around the surgical plans, showing that the surgeries were easier, and the patients had better time recovering, due to lower disease burden for those that got the combination with immunotherapy. And I think that's really, really exciting, because, I mean, it suggests a paradigm in the future where we can reduce the amount of surgery. So one of the things was they looked at the number of open thoracotomies versus VATS procedures. And a number of patients who got immunotherapy had a much lower surgical burden. So, I think those data are really exciting. They're not quite ready for prime time yet, because I think we need larger studies to prove this, but I think the trend is, we'll talk through these different disease settings, really does suggest that immunotherapy is going to really change all of oncology, in terms of surgical paradigms, how we follow patients, et cetera. ASCO Daily News: Excellent. Dr. Luke, you spoke earlier about the phase III study of relatlimab and nivolumab. There's another study, Abstract 9502 in the neoadjuvant setting, right? Dr. Jason Luke: Yep, and so, in addition to the phase III data for relatlimab, there was also a neoadjuvant study from The University of Texas MD Anderson Cancer Center group, which I think was really, really useful in helping us feel more confident actually about the metastatic disease data, and about understanding where the field in melanoma is going. So, in melanoma, that's where, sort of taking a step back quickly to note that there have been a whole bunch of neoadjuvant clinical trials done over the last 3 to 4 years, and actually so many that we've already started to have meta-analyses to look and see and observe, I should say, that those patients actually who have major pathologic responses, and those with complete responses, generally speaking, don't recur. And this is really exciting. It's actually even led to clinical trial designs where we're actually deferring surgery in melanoma, where we give neoadjuvant therapy. We take out one node. And if it's a complete response (CR) we don't even do the surgery. So in the Abstract 9502, again relatlimab, the anti-LAG-3 antibody was combined with nivolumab. And I think what the important thing to highlight here was that the rates of pathologic complete response and major partial response actually looked very similar to what we saw with nivo plus ipi in previous clinical trials. So if you remember, the relatlimab data in the metastatic setting was only the PFS data, due to the statistical plan. But what we see here is that in the neoadjuvant setting, very similar outcomes for relatlimab plus nivo as what would have been expected for ipi plus nivo. And I think that gives us, again, more strength and more confidence that this is a very active combo, again, with lower toxicity relative to nivo plus ipi. ASCO Daily News: OK, well, Abstracts 4503 and Abstract 4504 looked at alternative management strategies in bladder cancer. Can you tell us about these data? Dr. Jason Luke: So these were two really interesting abstracts, I thought, from my perspective. And they really looked at management, alternative management strategies for muscle invasive bladder cancer. And so the first one, 4503, was the Hoosier Oncology GU study 16-257. And this was a study that looked at neoadjuvant nivolumab plus gemcitabine and cisplatin, with an evaluation for clinical outcome. So what I mean by that was, after the patients got this treatment, they were evaluated for whether or not they had had a clinical complete response, and then they were offered the opportunity to either not pursue cystectomy, which obviously is highly morbid, or to continue to be followed. And, very interesting, the study, for those patients who were deemed to have had a complete clinical response, 70% of them did not recur. And that's really exciting, because if you think about the population of patients with bladder cancer, many of them elderly, those cystectomies are highly morbid surgeries. And this suggests that we may be able to move into a future where we could give them upfront medical therapy and actually potentially avoid that surgery. The other abstract I thought was really interesting was sort of married to that, which was the 4504 abstract. And that was a clinical trial that looked at the neoadjuvant administration of pembrolizumab plus gemcitabine chemotherapy and radiation treatment. And, again, what they observed in that study was very high rates of pathologic complete response, and longer term outcomes that looked very exciting. And I think what both of these studies show, as phase II studies, is the possibility that medical therapy might actually be curative in some patients. And there are a number of phase III efforts now ongoing to try to amplify these trials and actually confirm them on a larger scale. ASCO Daily News: Shifting our focus now to practice-changing trials in metastatic disease, GI oncologists were very pleased to see the data from CheckMate-648. What was observed in this trial, LBA 4001? Dr. Jason Luke: So CheckMate-648 in esophageal cancer was a study in the frontline metastatic setting, looking at the impact of immunotherapy plus chemotherapy, or immunotherapy alone versus chemotherapy. And so what I mean by that was one arm in the study looked at nivolumab with standard chemotherapy, compared to chemotherapy, and the other arm looked at nivolumab plus ipilimumab versus chemotherapy. And, very briefly, what was observed was that both of the active arms, so the immunotherapy containing arms, the nivo plus chemotherapy or the nivo plus ipi, both of them improved outcomes compared with chemotherapy. And so, moving forward, there's really no question now that the standard of care in the frontline management of esophageal cancer should include immunotherapy, either as a combination with chemotherapy, or possibly with leaving out the chemotherapy and giving just nivolumab plus ipilimumab. Now the sub-stratification of patients and their outcomes by sub-stage was important in this study, and again emphasized that it's mostly the PD-L1 positive patients who benefited the most from immunotherapy. So but the idea of potentially having a regimen that's chemotherapy-free for frontline esophageal cancer, I think is really exciting. And I'd be really interested to follow where this field goes in terms of which patients are getting selected for the nivo chemotherapy versus ipi plus nivo arms, in standard practice kind of moving into the future. And obviously further biomarkers will be really important. But I think this is really a practice-changing trial, again, to emphasize that all patients with esophageal cancer should be getting immunotherapy in the frontline, moving forward. ASCO Daily News: Indeed, what can you tell us about Abstract 6000 using camrelizumab for nasopharyngeal carcinoma (NPC)? Dr. Jason Luke: Yeah, absolutely. So I think that this is a really interesting study and I think important. This is a study actually looking at the impact of adding immunotherapy to chemotherapy in nasopharyngeal carcinoma. So all the oncologists in the United States will be like NPC, oh, yeah, I heard about that during fellowship. But this is actually a major source of morbidity and mortality throughout the rest of the world, especially in the developing world. And so this clinical trial to me is very interesting. So the short story here is that adding camrelizumab improved outcomes relative to chemotherapy, which I think is probably not surprising, because across many other settings we've seen that adding PD-1 to chemotherapy would improve outcomes. I think the difference here was that this is an antibody that was developed in China. And is it part of a growing trend to see competitor PD-1 PD-L1 antibodies entering the space. So to close the loop on NPC, I think these data really strongly suggest that we should be giving immunotherapy in combination with chemotherapy in the frontline to these patients. But I think, more broadly, start to open this conversation about how are we going to evaluate new drugs that are getting developed, say, only in China, or in other parts of the world where there are no patients from the United States that are actually participating in the clinical trial. Are those drugs going to get approved by the U.S Food and Drug Administration (FDA)? And if they do get approved by the FDA, how are they going to get priced, because as we're moving into the era now of more than 10 anti-PD-1, PD-L1 antibodies that have shown a benefit in the metastatic setting in phase III trials, one could imagine the time has finally come for price control, and not control, but price competition. It'll be really interesting to see whether or not that actually comes true. I don't know the answer yet. But this trial, I think, is very important in that regard. ASCO Daily News: And back to melanoma, can you tell us about advances in the metastatic setting? Dr. Jason Luke: Absolutely. So I think there were two to hit on quickly. Obviously there were more, but two quickly to hit on. One was Abstract 9506, which was the long term update, 6 and a half years of CheckMate-067, which people remember was the nivolumab plus ipilimumab versus ipi trial. And just to summarize this quickly, it really was amazing to see that now at 6 and a half years, we finally hit the median for overall survival for patients with metastatic melanoma in the frontline setting. And the median was 49%. So it just barely went under the median. But I just can't emphasize, when I was a fellow, and actually I'm a melanoma oncologist, and coming into this, the outcomes for patients at that time, the median survival was 9 months. And now we're talking about 10 years later, and the median is basically, it's 6 and a half years, almost 50%. So it's just outstanding. And I can't emphasize it enough. Clearly not good enough. We still have 50% of patients who need better treatments. But it's pretty exciting. The other abstract I wanted to highlight, because I think it differentiates where things stand, was the Abstract 9505, which was the tumor infiltrating lymphocyte (TIL) lifileucil in melanoma. And, again, just to highlight this, 36.5% response rate to re-infusion of TIL with interleukin-2. And I think that that's going to be an important part of the armamentarium for melanoma management, moving into the future. One final metastatic disease abstract to highlight was the development of T cell receptor (TCR) T cells for synovial sarcoma. So this was a really important abstract as well, going along with the lifileucil abstract, because I think this showed that this is a really active regimen with adoptive cell transfer for synovial sarcoma. And I would very much expect to see that both the TCR T cells and the TIL product get approved by the FDA within the coming year. ASCO Daily News: Excellent, well, before we wrap up the podcast, can you share some highlights from your main research area, developmental therapeutics? Dr. Jason Luke: Yeah, finally, so in the realm of developmental therapeutics, which is my major research area, there's always a lot going on. And I think this year's ASCO Annual Meeting I would just highlight a few things. So one is the continued development of VEGFR2 tyrosine kinase inhibitors (TKIs) with immunotherapy, we saw long term updates with lenvatinib and pembrolizumab in melanoma (Abstract 9504). And we saw other updates with new combinations in colorectal cancer. Another area in terms of considerations were small molecule inhibitors. And so there was a really interesting abstract about an MDM2 inhibitor. And people will remember that's a regulator of P-53, being combined with pembrolizumab. And preclinically and translationally, in this abstract, it appears that modulating the P-53 pathway via MDM2 actually has immunomodulatory effects. So it'll be very interesting to see where alrizomadlin goes (Abstract 2506).  There are a number of other novel targets. And there's so many abstracts on these that I'm not going to really go through them in a lot of detail. But TLR-7/8 agonism with checkpoint blockade looks interesting (Abstract 2512). There were a number of abstracts around transforming growth factor, TGF beta. And this is a really important target in cancer. And it'll be interesting to see how that gets developed out further. There were a number of approaches looking at targeting of human papillomavirus or HPV, one of them, which was a triplet regimen of an HPV vaccine plus a cytokine plus a PD-L1 antibody, and another one which was some viral vectors expressing HPV proteins. So all of this, I think, very interesting and taking sort of orthogonal to checkpoint approaches in terms of immunotherapy, vaccines, cytokines, viral vectors, et cetera. And then the final area, just to highlight, there was one very interesting Abstract 2507, which was a novel CAR T-cell product, which included a 41BB activation domain, attached actually to a bispecific CAR that binds to both CD19 and CD20. And this was Abstract 2507, and what I thought was very interesting was the rates of response for this molecule are really high, almost 100%. And that even included patients who had previously progressed on other CAR T products. So not enough time to go and give justice to any of these, but there's so much going on in developmental therapy for immuno-oncology. And I think that just emphasizes how bright the future is, building on this tremendous benefit in the standard of care setting in the adjuvant and metastatic settings. So, very excited to see where all these molecules go, and hopefully to advance the outcomes for all of our patients. ASCO Daily News: Indeed. Dr. Luke, thank you, as always, for your fantastic insight on some tremendous advances in immunotherapy, across the spectrum of malignancies. Our listeners will find links to all of the studies that you discussed in the transcript of this episode. Thank you, Dr. Luke. Dr. Jason Luke: Well, thanks so much for the opportunity. ASCO Daily News: And thanks to our listeners for joining us today. If you enjoyed this episode of the podcast, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. Jason Luke Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, and Arch Oncology Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, Immunocore, KSQ Therapeutics, Inzen, Pfizer, Silicon Therapeutics, TRex Bio Research Funding (Institution): Merck, Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Research Funding: Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., Trishula Therapeutics, BioNTech AG, Scholar Rock Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio Disclaimer: 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.

In the cover paper of this week's issue of Oncotarget (Volume 12, Issue 8), titled, "Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas," researchers examined five potential biomarkers across 18 different histologic subtypes of sarcoma in 163 tissue samples. Immunohistochemical staining, statistical analysis, and correlation-based network analysis revealed promising results. Researchers from the University of Iowa, University of Alabama at Birmingham, and the Mayo Clinic, report the need for additional prognostic and therapeutic biomarkers to predict clinical behavior across different histological types of sarcoma. “Although the French (FNCLCC) and NCI grading schemes have been adopted for many sarcomas, there is a substantial subset of sarcomas for which the grading scheme does not adequately predict clinical behavior.” Sign up for free Altmetric alerts about this article: DOI: https://doi.org/10.18632/oncotarget.27928 Full text: https://www.oncotarget.com/article/27928/text/ Correspondence to: Munir R. Tanas - munir-tanas@uiowa.edu About Oncotarget: Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Listen to short summaries of the latest oncology-focused research published in this week's issue of Oncotarget. https://www.oncotarget.com/archive/v12/i8/ Oncotarget Volume 12, Issue 8 features: COVER PAPER: “Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas” https://doi.org/10.18632/oncotarget.27928 NEWS: “Immunotherapy and fatigue: what we know and what we don’t know” https://doi.org/10.18632/oncotarget.27946 (PDF Download) EDITORIAL: “Drug exposure: still relevant after all these years” https://doi.org/10.18632/oncotarget.27899 (PDF Download) EDITORIAL: “Up to your NEK2 in CIN” https://doi.org/10.18632/oncotarget.27918 (PDF Download) RESEARCH PAPER: “Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®” https://doi.org/10.18632/oncotarget.27945 RESEARCH PAPER: “Insulin-like growth factor 1/Child-Turcotte-Pugh composite score as a predictor of treatment outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib” https://doi.org/10.18632/oncotarget.27924 RESEARCH PAPER: “Controlling for cellular heterogeneity using single-cell deconvolution of gene expression reveals novel markers of colorectal tumors exhibiting microsatellite instability” https://doi.org/10.18632/oncotarget.27935 RESEARCH PAPER: “Urine protein biomarkers of bladder cancer arising from 16-plex antibody-based screens” https://doi.org/10.18632/oncotarget.27941 RESEARCH PAPER: “The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations” https://doi.org/10.18632/oncotarget.27943 RESEARCH PAPER: “Loss of CPAP causes sustained EGFR signaling and epithelial-mesenchymal transition in oral cancer” https://doi.org/10.18632/oncotarget.27932 RESEARCH PAPER: “Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth” https://doi.org/10.18632/oncotarget.27940 RESEARCH PAPER: “Predicting clinical outcomes using cancer progression associated signatures” https://doi.org/10.18632/oncotarget.27934 RESEARCH PAPER: “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC” https://doi.org/10.18632/oncotarget.27930 About Oncotarget: Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com/ or follow us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/oncotargetyoutube Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget Oncotarget is published by Impact Journals , LLC. Please visit https://www.impactjournals.com/ or connect with us @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Do you suffer from seasonal allergies? Want to know how to deal with allergy symptoms naturally? Curious about the stress connection to worsened seasonal allergies? Tune in to hear Ali and Becki discuss why seasonal allergies happen, who is most susceptible and what you can do to reduce symptoms and heal from the root cause!    In this episode, Ali and Becki take a deep dive on seasonal allergies, from the influence of stress to what allergies can tell us about the state of your gut. Learn about foods to avoid during allergy flares as well as those to include to help reduce symptoms and reactivity. Hear our take on conventional allergy medications, allergy testing and allergy shots. Plus get supplement recommendations to not only mitigate symptoms but help your body become resilient to seasonal allergies!    Also in this episode: Subscribe to the Naturally Nourished Newsletter Naturally Nourished YouTube Channel Episode 185: Histamine Intolerance with Dr. Becky Campbell Episode 68: Supporting Your Immune System Episode 199: The Importance of Breath Why Seasonal Allergies Occur Symptoms of Seasonal Allergies Who is Most Susceptible to Seasonal Allergies The Influence of Stress on AllergiesAdrenal Support Adaptogen Boost Cordycepin Suppresses Thymic Stromal Lymphopoietin Expression via Blocking Caspase-1 and Receptor-Interacting Protein 2 Signaling Pathways in Mast Cells TSLP induces mast cell development and aggravates allergic reactions through the activation of MDM2 and STAT6 The Gut Connection to Seasonal AllergiesBeat the Bloat Cleanse MRT Test Gi Lining Support Foods that Influence AllergiesDry Farm Wine use code ALIMILLERRD for a Penny Bottle!  Side Effects of Conventional Allergy Medications Thoughts on Allergy Testing & Allergy Shots Supplement StrategyCellular Antiox Bio-C Plus  Inflammazyme Rebuild Spectrum Probiotic EPA DHA Extra Orthomolecular D-Hist Texas Tree Formula XClear Nasal Spray Food As Medicine for Allergy Support40 Clove of Garlic Soup Hot Toddy Master Tonic Spirulina Pique Tea use code ALIMILLERRD for 10% off  ReferencesPatterson AM, Yildiz VO, Klatt MD, Malarkey WB. Perceived stress predicts allergy flares. Ann Allergy Asthma Immunol. 2014 Apr;112(4):317-21. Roschek B Jr, Fink RC, McMichael M, Alberte RS. Nettle extract (Urtica dioica) affects key receptors and enzymes associated with allergic rhinitis. Phytother Res. 2009 Jul;23(7):920-6.   Sponsors for this episode:  This episode is sponsored by Nutrisense, providing Continuous Glucose Monitors (CGM) that provide you with real-time glucose data and an easy to use phone app that helps you combine and visualize your glucose data with all of your daily activities as well as personalized recommendations on how to improve your health. Use the code AliRD for $30 off your monthly subscription plan at nutrisense.io.

William Sukov, M.D., provides an overview of the MDM2 gene amplification assay — a test that looks for amplification of the MDM2 gene region on chromosome 12q. He reviews when this test should be ordered, how it compares to other test options, and how its results can affect patient care.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, 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. Dr Carolyn Lam: Greg, our feature paper today talks about the risks of sudden cardiac death, something that we still grapple with, and do you know what, really highlights the important emerging role of biomarkers of myocardial stress, myocardial injury, or even subclinical inflammation in predicting this risk. A really important discussion coming right up. But before we do that, let me tell you about a paper in today's issue that really provides novel mechanistic insights into atrial fibrillation pathogenesis. In fact, this is the first paper to demonstrate that decreased expression of a striated muscle preferentially expressed protein kinase, or SPEG in atria, is causally linked to altered diastolic calcium handling and human paroxysmal atrial fibrillation. This is from corresponding author, Dr Wehrens and colleagues from Baylor College of Medicine. And they used phosphoproteomic studies to identify S2367 on ryanodine receptor type-2 as a novel kinase substrate of SPEG. Through the study of novel ryanodine receptor type-2 phospho-mutant mouse models, they revealed that in contrast to previously characterized phosphorylation sites on this receptor, S2367 phosphorylation inhibited diastolic calcium release from the receptor, while loss of phosphorylation of the site increased atrial fibrillation susceptibility. Dr Greg Hundley: Wow, Carolyn. So the clinical implication is that normalizing S2367 phosphorylation in SPEG activity may provide novel therapeutic opportunities for the treatment of atrial fibrillation, right? Dr Carolyn Lam: You bet, Greg. Too smart. And this is discussed in an accompanying editorial by Drs Knollmann and Blackwell from Vanderbilt University Medical Center. Dr Greg Hundley: Very nice, Carolyn. Well, I've got a paper pertaining to COVID-19, and it comes to us from Dr Leo Nicolai from the Klinik der Universität München in Germany. Carolyn, I really enjoyed this article about COVID-19. I found it very intriguing, and the study addresses the mechanisms by which the SARS-CoV-2 infection, associated pneumonia or COVID-19, leads to subsequent respiratory failure, complicating renal and myocardial involvement, and the prothrombotic phenotype found in some patients with COVID-19. 62 subjects were included in the study, 38 patients with RT-PCR confirmed COVID-19 and 24 non-COVID-19 controls. The investigative team performed histopathological assessments of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet-neutrophil functions and coagulation tests. Dr Carolyn Lam: Wow, that sounds like really sort of in-depth testing. And what did they find? Dr Greg Hundley: Several things, Carolyn. First, the authors found evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. They found that in COVID-19 patients, inflammatory microvascular thrombi are present in the lung, kidney and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Second, they observed that COVID-19 patients also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood which changes with disease severity, whereas cases of intermediate severity show an exhausted platelet and hyperreactive neutrophil phenotype. This finding differs for severely affected individuals. Among severely affected COVID-19 patients, there is excessive platelet and neutrophil activation compared to healthy controls and non-COVID-19 pneumonia. Finally, dysregulated immunothrombosis in SARS-CoV-2 pneumonia is linked to both ARDS and systemic hypercoagulability. So in conclusion, taken together, this team's data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19, and further work is suggested to identify methods to disrupt immunothrombosis in patients with COVID-19. Dr Carolyn Lam: Wow. That makes a lot of sense and is important information. Thanks, Greg. Well, this next study really aimed to assess the current trends in US mortality related to congenital heart disease from infancy to adulthood over the last 19 years, and to determine if there were differences by sex and ethnicity. This is from Dr Lopez from Texas Children's Hospital and Baylor College of Medicine and colleagues who conducted an analysis of death certificates from 1999 to 2017, and also used data from the National Center for Health Statistics' live birth data and US Census Bureau bridged-race estimates as denominators for these population estimates. Dr Greg Hundley: Wow, Carolyn. Really interesting article. So what did they find here? Dr Carolyn Lam: So overall, US mortality due to congenital heart disease throughout the lifespan has decreased over the last 19 years, with the greatest mortality rate in infants. Disparities in mortality due to congenital heart disease persists for males compared to females, with men having higher mortality than women, and for non-Hispanic blacks compared to non-Hispanic whites. For those less than 50 years old with congenital heart disease as a contributing cause of death, associated genetic abnormalities are the leading underlying cause of death, whereas myocardial infarction was the leading cause of death in those 50 years and older. And so, the authors also concluded that determining factors that contribute to these disparities, such as access to quality care, timely diagnosis and maintenance of insurance, will be very important moving into the next decade. Dr Greg Hundley: Boy, that is such a timely topic. Beautiful presentation. Dr Carolyn Lam: Thanks, Greg. And now for my last paper. We've heard a lot recently about angiotensin-converting enzyme 2, or ACE2, that’s that membrane protein that enables COVID-19 infectivity and which also converts angiotensin II, which is a potent vasoconstrictor, to angiotensin 1-7. Now, today we've got a paper that provides novel insights into the contribution of ACE2 to the development of pulmonary arterial hypertension. And this is from Dr Shyy and Yuan as co-corresponding authors from the University of California, San Diego, as well as Dr Yuan 00:08:06 from First Affiliated Hospital of Xi'an Jiaotong University in China. The authors used cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension to investigate the post-translational modification of ACE2 in terms of, firstly, phosphorylation by AMP-activated protein kinase, which enhances ACE2's stability, and two, ubiquitination of oncoprotein murine double minute 2, or MDM2, which is involved in ACE2 degradation. Dr Greg Hundley: So what did they find here? Dr Carolyn Lam: MDM2 expression was increased in lung tissues from patients with idiopathic pulmonary arterial hypertension and animals with experimental pulmonary hypertension. On the other hand, N-kinase phosphorylates ACE2 at S680 and inhibits MDM2- mediated ubiquitination of ACE2 at K788. Functionally, ACE2 phosphorylation and deubiquitylation increases eNOS-mediated nitric oxide bioavailability in the endothelial cells. Dr Greg Hundley: Okay, Carolyn. What are the clinical implications here? Dr Carolyn Lam: So post-translational modification of ACE2 is a novel strategy to develop new therapies for pulmonary arterial hypertension. On the other hand, inhibition of MDM2 has great potential for pulmonary arterial hypertension by stabilizing ACE2. Dr Greg Hundley: Wow, beautiful summary there. Let me describe some of the other articles in the issue. First, Dr Jawad Butt has a research letter regarding the impact of COVID-19 on first-time acute stroke and transient ischemic attack admission rates and prognosis in Denmark. It's from a nationwide cohort study. Next, there's an exchange of letters regarding the article, preventive or deferred ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and an implantable defibrillator, the Berlin VT multicenter randomized trial. And that comes to us from Drs Krisai and Kuck. Next, there's a very nice ECG challenge from Dr Arrey-Mbi wide complex QRS rhythm in a 52-year-old male with an altered mental status. And then finally, a nice case series from Dr Oscar Cingolani, entitled, ECMO therapy for cardiac lymphoma. Dr Carolyn Lam: Well, I've also got a research letter by Dr Verdonschot on distinct cardiac transcriptomic clustering in titin and lamin-associated dilated cardiomyopathy patients. There's also a white paper by Dr Butler on glucagon-like peptide-1 receptor agonists and heart failure, highlighting the need for further evidence generation and practice guidelines optimization. And finally, an On My Mind piece by myself and Dr Butler entitled, “Victims of Success and Failure,” where we really describe how, with so many effective therapies for HFrEF these days, have we become victims of our own success?   Dr Greg Hundley: Very nice, Carolyn. Well, how about we get on to that feature and hear a little bit more about myocardial stress injury and the association with sudden death? Dr Carolyn Lam: Yes. Let's go, Greg. Sudden cardiac death is the most common cause of death in the United States but identifying individuals at risk before they suffer a fatal event remains really challenging. In fact, it's the sad truth that the majority of sudden cardiac deaths occur in low-risk populations, often as the first manifestation of cardiovascular disease. Now, can biomarkers help us identify those at risk of sudden cardiac death? Well, you have to listen to our discussion of today's feature paper, a beautiful paper that I'm so pleased to be welcoming the first and corresponding author, who's also our associate editor, Dr Brendan Everett from Brigham and Women's Hospital, who will talk about it, as well as our guest editor, Professor Harvey White, who is director of research at the Green Lane Cardiovascular Service in Auckland, New Zealand. So welcome, gentlemen. And Brendan, could I get you to start by telling us what you did in this study and what you found? Dr Brendan Everett: We were interested in exploring this problem. Dr Albert, Christine Albert, who is the senior author on the paper, has years of experience looking at sudden cardiac death as an important outcome amongst patients who may not have yet been diagnosed with cardiovascular disease. And of course, as you mentioned in your introduction, it can be the first manifestation of cardiovascular disease. And because we, as physicians, don't get a chance to then help patients recover and treat them for their cardiovascular disease, we often feel like we've missed the opportunity to help people live longer and more productive lives. The problem, of course, with this is that there's a huge population of people who are at risk, but actually identifying tests that will work well enough and can be used in a broad population, who, in aggregate, are actually at low individual absolute risk, is very challenging. The markers that we selected to study for this paper included measures of lipids, in this case, total cholesterol, the HDL cholesterol, NT-proBNP, a marker of myocardial stress, which is, I'm sure, familiar to many people on the podcast, high-sensitivity cardiac troponin I, which again, is increasingly used throughout the world, including here in the United States, and hsCRP, a marker of subclinical inflammation. I think the advantage that we had is that, over the years, Dr Albert has compiled a number of cases of sudden cardiac deaths in cohorts that have been followed prospectively for a long period of time. These are NIH-funded cohorts and include studies that may be familiar to your listeners, like the Nurses' Health Study, the Physician's Health Study I and II, the Women's Health Study. These are cohorts that have been following patients for, in some cases, decades, and of course, when you have a lot of patients or participants and you follow them over many years, some of them die suddenly. Not very many, fortunately, but enough so that if you aggregate all six cohorts together, you can have a total of, in our case, 565 cases, which is more, I think, as far as I know, anyways, than other cohorts that are out there that have studied this question. We were able to match those two-to-one with 1090 controls, and then measure the biomarkers I mentioned earlier in all of those patients, and then look at the association between those common, relatively accessible biomarkers and the risk of sudden death. Dr Carolyn Lam: Congratulations. I do think this is the largest collection of sudden cardiac death cases, as well as with prospectively collected blood samples. And I do believe yours is the first to really have a multi-marker approach. So now, could you tell us what you found? Dr Brendan Everett: We first assessed each of these four markers individually and found that their risk of sudden cardiac death was relatively strong and was independent of other traditional cardiovascular risk factors, such as cigarette smoking or body mass index and those sorts of things. It appeared, at least in our analysis, that NT-proBNP and cardiac troponin might have been slightly more powerful correlates of the risk of sudden cardiac death in total to HDL cholesterol ratio in hsCRP. But nonetheless, when we put them all together in a comprehensive model, we found that the risk estimates for each individual marker were maintained. In other words, they were independent of one another and they all remained statistically significant. So this tells me, as a cardiologist and an epidemiologist, that we're getting a sense of somebody's risk from multiple different perspectives. We're integrating that information, and then potentially, when we combine those markers together, have the opportunity to have an improved ability to identify individuals at risk. And so, that's actually what we did, and I think this is what you're asking about. We decided to create a very simple biomarker score where we gave each participant one point if their concentration of a given biomarker was in the top core tile of that biomarker's range, so the top 25%. So just by way of example, if somebody had all normal biomarkers except for a high total cholesterol, the HDL ratio, they would get one point. The total number of points, of course, could range from zero to four, and then we looked at what the risk of sudden cardiac death was across that scale. And what we found is that it went up in a relatively linear fashion. The odds ratio increased by about 1.6 per individual point of score increase, such that, for example, compared to those individuals with a score of zero, who of course, had normal concentrations of these four biomarkers, if you had all four be elevated, your odds ratio of sudden cardiac death was actually seven. If you just had three out of the four being abnormal, it was approximately four. So those participants with at least three or four abnormal concentrations of these biomarkers seemed to be at a high relative risk or odds ratio for sudden cardiac deaths. Dr Carolyn Lam: Ah. Love it, Brendan. And for all of you who are listening, you have to pick up the paper and look at the figures. The story is all there, the individual biomarkers and that score. I love the simplicity and the clarity of the message. Harvey, could you summarize for us and perhaps give us a sneak peek of the discussions that occurred behind the scenes when this paper landed on your desk? Dr Harvey White: When I saw this paper, it was terrific. And I had to decide whether to get reviewers who are experts in sudden death, or are experts in cholesterol, or troponin, or each of the four biomarkers, and I chose to get people who are interested in sudden death. And I had three reviewers, and they all said it was absolutely terrific, elegant study, robust data. They focused on the cut points, for example, NT-proBNP. Initially, Brendan, you looked at the median for your study, and the reviewers said, "Well, can we look at clinically relevant?" So they requested that you consider that, and I must say, your responses were just terrific. And so, you went to a cut point of 125, which is clinically relevant. I think this is extraordinarily important. The reviewers stressed that you should be careful with your conclusions. And you carefully said, "This represents only the first step in testing whether these biomarkers may serve as valuable clinical tools." I would go further than that. I think these four tests are inexpensive, they're clinically available. I don't do them on all patients, but I do them on some. I always do lipids, and I do NT-BNP in somebody with heart failure or decreased ejection fraction. And I always do troponin, which I think is extremely important. Even in the normal range, it trebles its risk. So a question to Brendan. I think if I found a high troponin, I want to look at CRP, look at NT-proBNP, and I'd have the cholesterol HDL ratio. So what would you think about cascade screening and the implications of that on cost effectiveness? Dr Brendan Everett: I think that's a really excellent suggestion. We hadn't thought of that, as you know, and it doesn't come up as an idea in the discussion. I think, at least here in the United States, the standard test would be a total cholesterol to HDL ratio, and of course, with that, oftentimes in LDL cholesterol, because that's where we focus our preventative efforts with statins, as you mentioned. And we typically would not do a troponin in otherwise healthy and ambulatory patients. I think that's a creative suggestion, the idea that if you had an abnormal cholesterol, and then an abnormal NT-proBNP, and then would you move to a CRP and a troponin as well? I think in the type of patient that we're talking about, a primary prevention patient who may have occult cardiovascular disease, CRP is probably the best validated, epidemiologically, as a marker of risk and to guide therapy. But I think one thing that we struggled with, and I'd be interested in your view on this because you're such an expert on cardiac troponin, is, what are the therapeutic interventions that you would use for somebody with an elevated biomarkers for... And we addressed this a little bit in the discussion, and I think it's just common sense preventive therapy, but I don't know if that struck you as the right thing to do, or if you had other ideas about how to address somebody who might have, theoretically, an elevated risk of sudden cardiac death. Dr Harvey White: I think it's challenging common sense. Do people use them? So I think the stress should be that preventive therapy should be used in these patients. So blood pressure and history of hypertension is related to sudden death. In your study, sudden death was more common in individuals who didn't exercise. Obviously, they're higher cholesterol, so you got to promote weight loss, blood pressure, nonpharmacological means diabetes is associated with, and a higher HbA1c, so you really want to get the HbA1c down. Whenever you find an abnormal troponin, you need to go back to the patient and get an echocardiogram. Have they got left ventricular hypertrophy? Have they got underlying LV dysfunction, and so forth? And to get the patient on board, one of the things that you would challenge with doing is the drug use during follow up. And I was particularly interested in beta blockers, which of course, may reduce sudden death. But I'm also interested in, about 30% of patients with sudden death have taken cocaine or alcohol. And so, addressing drug use is important, addressing alcohol is important. And just as an add-on in this age of COVID, don't take hydroxychloroquine, because that might cause sudden death. Dr Carolyn Lam: Harvey and Brendan, those were just really excellent points. In fact, I was sort of thinking along the same lines of, what are the therapeutic implications of this? And I think one of the management implications addresses one of the limitations, perhaps though, because this study did not include electrocardiographic or imaging information, like left ventricular ejection fraction. I just wanted to double-check if that's the case, Brendan. And if you could, how has this impacted your own practice, or what's the next steps, you think? Dr Brendan Everett: You are absolutely correct, that as a routine, none of the studies that we included in this research work actually had baseline electrocardiograms or echocardiograms. I think when you take the perspective of wanting to screen or thinking about screening a broad population for the risk of sudden cardiac death, an echocardiogram is probably not a feasible study. Although, to Harvey's earlier point and to your own point, using that as a subsequent test, along the lines of the cascade screening approach, when you have an abnormal cardiac troponin or an abnormal NT-proBNP, perhaps an echocardiogram is a very good study to order at that point. The lack of electrocardiograms, I think, is another limitation of our work. Those are more commonly used, at least I think, as a screening tool, at least in the United States, when somebody has a history of hypertension, for example. I think, with respect to your last question, "How has it changed my own practice?", I think the key thing that I wanted to emphasize, which is an important limitation of the study, is that this is a case control study. So what we're able to do is, we're able to estimate relative risks. And relative risks of seven are high. They're impressive, right? The problem is that we can't actually estimate what the absolute population risk is of sudden death based on the patients or the participants in these studies. So it's hard to take the group of participants that we were able to look at and watch carefully prospectively, and then back-calculate what the absolute risk of sudden cardiac death would be in a broader population. So in order to take a research finding like this, where there's a high relative risk, and start to think about population-wide screening, you have to know how that will implicate or affect the absolute risk. If your absolute risk is tremendously low, seven times tremendously low is still tremendously low. However, if you can find a population where a relative increase of seven in your absolute risk actually becomes clinically important, then you begin to have an argument about population screening and whether or not it's worthwhile and effective, or potentially how it can reduce the occurrence of sudden death, which is our goal, after all, with a study like this. Dr Carolyn Lam: What a balanced discussion. So thank you, Brendan. That was a very important point. Finally, are you planning next studies, or what's the next step then, you think? Dr Brendan Everett: Well, I think the next step would be to try and figure out how to translate the data that we have here into a real sense of how this would affect absolute risk. This would then have implications for cascade screening, as Harvey mentioned earlier, potentially broader use of these biomarkers as screening tools in otherwise healthy populations, and of course, implications, both about the testing characteristics and false positives and those sorts of important issues, and then the cost and the cost effectiveness, how much it would cost to screen such and such a population to prevent one sudden cardiac death. Those would all be the next steps, I think, in terms of determining whether or not this approach could be implemented more broadly. Dr Carolyn Lam: Thanks, Brendan, and thank you so much for this paper. It's just so beautifully and elegantly put. It's something I'm going to remember and already taken my clinical practice to recognize persons at risk and whom I want to do further work of. Thank you so much for joining us today, Brendan. Thank you so much, Harvey. And thank you, audience, for listening today. Please tune in again next week. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

Myeloproliferative Neoplasms Update — Part 2: Our interview with Dr Gerds highlights the following topics and cases from his practice: Common misconceptions about MPNs (0:00) Alterations of the JAK-STAT signaling pathway in MPNs (1:43) Case: A 61-year-old woman with primary MF and mutations in JAK2, EZH2 and CALR receives ruxolitinib (4:29) Prognostic significance of the JAK2, EZH2 and CALR mutations associated with MF (7:20) Dosing and activity of ruxolitinib for MF (8:53) Management of ruxolitinib-associated cytopenias and effect of ruxolitinib on disease pathogenesis (12:19) Evolution of clinical research with the selective JAK2 inhibitor fedratinib for MF (15:32) Association between fedratinib and thiamine levels; cytopenias associated with fedratinib (17:20) Efficacy of fedratinib as second-line treatment for patients with disease progression on ruxolitinib (18:38) Risks and benefits associated with pacritinib therapy (20:00) Case: A 66-year-old man who presents with anemia is diagnosed with MF and a Type 1 CALR mutation (21:48) Risk of infections associated with ruxolitinib (23:12) Evaluation of ruxolitinib for the treatment of graft-versus-host disease (27:05) Activity of the JAK1/2 inhibitor momelotinib in patients with MF (28:23) Hepcidin suppression and improvement of anemia in patients with MF; effect of novel JAK inhibitors, including fedratinib and momelotinib (30:03) Results of the SIMPLIFY 2 study evaluating momelotinib versus best available therapy for patients with MF previously treated with ruxolitinib (32:28) Use of JAK inhibitors for rheumatoid arthritis (35:29) Novel agents and approaches under investigation for MPNs (36:48) Perspective on the potential role of venetoclax for patients with MPNs (40:30) Case: A 75-year-old woman previously diagnosed with ET and a JAK2 V617F mutation is found to have disease transformation to PV on reassessment 12 years later (43:34) Efficacy and side effects of the MDM2 antagonist idasanutlin in the treatment of PV (47:36) Importance of maintaining hematocrit control in patients with PV (50:15) Role of ruxolitinib for patients with PV (51:55) Case: A 45-year-old woman with persistent headaches is diagnosed with ET and a JAK2 V617F mutation (54:08) Therapeutic options for patients with ET (56:47) Perspective on the need for aspirin for ET (59:17) Role of interferon and PI3-kinase inhibitors in the treatment of MPNs (1:00:37) Select publications

Vitamin D kann entweder durch die Nahrung aufgenommen oder durch UV- Bestrahlung der Haut aus 7-Dehydrocholesterol gebildet werden. Das entstehende inaktive Vitamin D3 wird anschließend durch die 25-Hydroxylase (CYP2R1) in der Leber zu 25-Hydroxyvitamin D3 (25D) metabolisiert. 25D ist die vornehmlich zirkulierende Form von Vitamin D, es selbst besitzt allerdings nur etwa ein Tausendstel der Aktivität der endgültigen, aktiven Form des Hormons, 1α,25- Hydroxyvitamin D3 (1,25D), das überwiegend in der Niere durch die mitochondriale Hydroxylase CYP27B1 produziert und im Plasma durch Interaktion mit DBP (plasma vitamin D binding protein) stabilisiert und transportiert wird. Die Hauptfunktion von 1,25D besteht offenbar in der Bindung an das intrazelluläre Protein Vitamin D Rezeptor (VDR), welches daraufhin typischerweise mit einem zweiten Protein, dem Retinoid X Rezeptor, heterodimersisiert und dann gemeinsam mit diesem an sogenannte Vitamin D response elements (VDREs) in der DNA bindet. Die weiteren Konsequenzen dieser Bindung sind nicht in allen Einzelheiten verstanden, führen aber entweder zur transkriptionellen Aktivierung oder Reprimierung einer großen Anzahl von Gensequenzen. Die E3 Ubiquitin-Ligase und Transkriptionsrepressor MDM2 ist ein potenter Inhibitor der p53 Familie von Transkriptionsfaktoren, Stoffwechselregulatoren und Tumorsuppressoren. Es konnte mit dieser Arbeit gezeigt werden, dass der VDR ein weiterer Transkriptionsfaktor, Stoffwechselregulator und Tumorsuppressor ist, welcher ebenfalls von MDM2 gebunden und inhibiert wird. Es stellte sich heraus, dass der VDR in der Zelle zum Teil durch MDM2 ubiquityliert wird, seine Steady-State Level durch das Proteasom kontrolliert werden und ein Knockdown von endogenem MDM2 die VDR-Level erhöht. Ein Knockdown von MDM2 führte zu einer signifikanten Erhöhung des Transkripts der Gene CYP24A1 und p21, klassische zelluläre Ziele der Transaktivierung durch ligandengebundenen VDR. Die Ergebnisse dieser Arbeit legen nahe, dass MDM2 analog zu p53 den VDR negativ reguliert.

Murine double minute (MDM)-2, an E3 ubiquitin ligase, promotes cancer cell survival and growth, by degrading the cell cycle regulator p53. Antagonism of MDM2 by the small-molecule cis-imidazoline nutlin analogs is currently under study for cancer therapy. We observed that MDM2 is strongly expressed by the epithelial cells in the kidney for example, tubular epithelial cells and podocytes. To test whether MDM2 promotes regenerative cell growth, we studied the effects of MDM2 antagonist, nutlin-3a on tubule cell healing during postischemic acute kidney injury and on podocytes during adriamycin induced chronic renal failure. Consistent with the hypothesis, we observed that treatment with nutlin-3a impaired tubular cell regeneration during postischemic AKI in C57Bl6 wild-type mice in a p53-dependent manner. However, MDM2 blockade also prevented tubular necrosis by suppressing sterile inflammation during the early postischemic phase. This effect also occurred in p53-deficient mice, indicating a second, pro-inflammatory, p53-independent role for MDM2 in AKI. In-vitro experiments confirmed that MDM2 is required to induce mRNA expression and secretion of NF-κB-dependent cytokines upon Toll-like receptor stimulation by enhanced binding of NF-κB to cytokine promoter–binding sites. Thus, MDM2 links inflammation and epithelial healing during AKI. It promotes the inflammatory response after the injury at the same time it drives the regeneration of injured tubular epithelium. Therefore, these additional biological functions need to be regarded when considering MDM2 inhibition therapy in patients with acute renal failure. Since, podocytes strongly express MDM2, we hypothesized that blocking MDM2 during glomerular injury may enhance podocyte apoptosis, proteinuria and glomerulosclerosis. However, unexpectedly MDM2 blockade in early adriamycin nephropathy in Balb/c mice had the opposite effect and reduced intrarenal cytokine and chemokine expression, glomerular macrophage and T cell counts, plasma creatinine and BUN levels. In cultured podocytes exposed to adriamycin, MDM2 blockade did not enhance podocyte apoptosis but rather prevented aberrant nuclear divisions and death of aneuploid podocytes, i.e. mitotic catastrophe. Accordingly, MDM2 blockade induced p21 and prevented podocyte mitosis in-vivo while TUNEL+ apoptotic podocytes were not detected. Thus, mitotic catastrophe is a previously unrecognized variant of podocyte loss where MDM2 promotes podocytes to complete the cell cycle, which in the absence of cytokinesis, leads to podocyte aneuploidy and death. Furthermore, delayed MDM2 blockade also reduced plasma creatinine levels, BUN, tubular atrophy, interstitial leukocyte numbers and cytokine expression as well as interstitial fibrosis. Together, MDM2 blockade with nutlin-3a could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease. In conclusion, therapeutic MDM2 blockade may hold the risk of impaired epithelial healing in AKI. On the other hand it may delay or halt the progression of glomerular disorders to CKD by reducing renal inflammation and by directly protecting podocytes from cell death by mitotic catastrophe.

Sat, 21 Jul 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15180/ https://edoc.ub.uni-muenchen.de/15180/1/Hagedorn_Caroline.pdf Hagedorn, Caroline

The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis. We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking. Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7-1.5) and 1.0 ( 95% CI: 0.7-1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences.