Podcasts about bcl xl

BUFFALO, NY- March 25, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.” ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. In this new study, researchers Benigno C. Valdez, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center and the University of Alberta demonstrate the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. “The results may provide relevant information for the design of clinical trials using these drugs to circumvent recognized drug-resistance mechanisms when used as part of pre-transplant conditioning regimens for AML patients undergoing allogenic HSCT.” Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. “The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.” DOI - https://doi.org/10.18632/oncotarget.28563 Correspondence to - Benigno C. Valdez - mbalasik@yahoo.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28563 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, acute myeloid leukemia, aml, pre-transplant regimens, venetoclax, thiotepa, busulfan 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. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital 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- March 6, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on March 5, 2024, entitled, “GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.” In this new study, researchers Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, in multiple myeloma cells. GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. “GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent.” The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. “Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.” DOI - https://doi.org/10.18632/oncotarget.28558 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28558 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, bortezomib, proteasome inhibitor 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- February 26, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 8, 2024, entitled, “GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.” In this new study, researchers Michael R. Booth, Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated the therapeutic agent GZ17-6.02, composed of curcumin, harmine and isovanillin. “Combined with our curcumin findings, we believe that isovanillin can complex with curcumin and harmine to create an entity with unique biology when compared to the three individual agents.” GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not previously been studied. The researchers found that GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. “All three components are necessary for optimal killing of MF cells.” GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, the team wrote that GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.” “We discovered that GZ17-6.02 containing harmine, isovanillin and curcumin caused more tumor cell killing than any of the agents individually or in pairs, and that it could interact in an additive fashion with standard of care MF drugs such as bexarotene and vorinostat to cause additional tumor cell death.” DOI - https://doi.org/10.18632/oncotarget.28557 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28557 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, bexarotene, vorinostat 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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.28.550973v1?rss=1 Authors: Edwards, F., Fantozzi, G., Simon, A. Y., Morretton, J.-P., Herbette, A., Tijhuis, A. E., Wardenaar, R., Foulane, S., Gemble, S., Spierings, D. C. J., Foijer, F., Mariani, O., Vincent-Salomon, A., Roman-Roman, S., Sastre-Garau, X., Goundiam, O., Basto, R. Abstract: Centrosome amplification is a feature of cancer cells associated with chromosome instability and invasiveness. Enhancing chromosome instability and subsequent cancer cell death via centrosome unclustering and multipolar divisions is an aimed-for therapeutic approach. Here we show that centrosome amplification favors responses to conventional chemotherapy independently of multipolar divisions and chromosome instability. We perform single-cell live imaging of chemotherapy responses in epithelial ovarian cancer cell lines and observe increased cell death when centrosome amplification is induced. By correlating cell fate with mitotic behaviors, we show that enhanced cell death occurs independently of chromosome instability. We identify that cells with centrosome amplification are primed for apoptosis. We show they are dependent on the apoptotic inhibitor BCL-XL, and that this is not a consequence of mitotic stresses associated with centrosome amplification. Given the multiple mechanisms that promote chemotherapy responses in cells with centrosome amplification, we assess such a relationship in an epithelial ovarian cancer patient cohort. We show that high centrosome numbers associate with improved chemotherapy responses and longer overall survival. Our work identifies apoptotic priming as a clinically relevant consequence of centrosome amplification, expanding our understanding of this pleiotropic cancer cell feature. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in melanoma, including targeted therapy and the addition of LAG-3 inhibitors to checkpoint therapy, as well as promising checkpoint inhibitors in cutaneous squamous cell carcinoma and Merkel cell carcinoma in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to welcome my colleague and friend, Dr. Jason Luke. Dr. Luke is an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh's Hillman Cancer Center. He is a very, very well-renowned physician-scientist who has done fundamental work in developmental therapeutics and also in melanoma.  Today, we'll be discussing some key oral abstracts highlighting advances in immunotherapy in the cutaneous malignancy space that will be featured at the 2023 ASCO Annual Meeting.   You will find our full disclosures in the transcript of this episode and the disclosures of all guests on the ASCO Daily News Podcast are available in our transcripts at asco.org/DNpod.  Jason, thank you for coming on the podcast today. Dr. Jason Luke: Well, thanks so much for the opportunity. Dr. Diwakar Davar: So, we will go right ahead into the abstracts and the first one we thought we'd discuss is Abstract 9502, which is the RELATIVITY-047 study, specifically the 2-year results. This is the update. This has also been concurrently published at the New England Journal of Medicine Evidence online. And so in this publication and oral presentation, Hussein Tawbi, Georgina Long, and colleagues are talking about the nivo-rela data in the context of metastatic melanoma. So what is your take on this? What is your take on the data both presented and published and how would you contextualize this for the audience? Dr. Jason Luke: Right, so the RELATIVITY-047 study, as people will remember, randomized treatment-naive patients with metastatic melanoma to either receive nivolumab as standard treatment as a monotherapy or the combination of nivolumab and the anti-LAG-3 antibody relatlimab. And that study reported out a couple of years ago showing the improvement in progression-free survival as the primary endpoint. And at the time we saw that difference was approximately a 6-month absolute difference. And eventually, we saw there was an increase in the overall response rate also, again, approximately on the order of about a 10% change. What was interesting was that the overall survival initially was immature and that was an interesting follow-up point that we wanted to see. So I think what's important in seeing now this 2-year update of these data are the maintenance of the benefit for nivolumab plus relatlimab as compared to nivolumab alone across those measurements of progression-free survival and overall response rate.  Interestingly, the overall survival in the clinical trial actually did not meet the pre-specified threshold for statistical significance. That being said, when you look at the data presented in the Kaplan-Meier plots and you think about the difference, it really does appear that there's a clinically meaningful difference between these 2 groups. And the statistical cut point only missed by about .01. And so this is one of those areas where one wonders whether or not subsequent therapies may have impacted on the overall survival calculation because obviously, patients in this trial had not received ipilimumab or a PD-1 CTLA-4 combination. So the take-home message from me in this data set was that the benefit of nivolumab and relatlimab was sustained over time and there was no suggestion of any late toxicities that might make us concerned.   One advantage of this combination of nivolumab and relatlimab is the dramatically improved side effect profile relative to nivolumab and ipilimumab. So whereas immune-related adverse events that were serious, grade 3-4 is approximately 50% for nivolumab and ipilimumab, in the RELATIVITY-047 study, we see that the incidence of grade 3-4 toxicities for nivolumab and relatlimab is 17.2%, so that's less than half. So that's pretty attractive. And when we think about frontline management of patients, I think these data really support that nivolumab plus relatlimab is a reasonable consideration for some patients. And now I think the future question is really going to be, okay, well then who should get nivolumab and relatlimab versus who should still get nivolumab plus ipilimumab? Obviously, these data do not address that, and I think that that's probably the most important question for metastatic disease that's probably on the horizon. Dr. Diwakar Davar: Thank you, Jason, those are all fantastic points. It is interesting to note that as a result of the data, or really the lack thereof, the combination is actually not being launched in certain countries. So, for example, the German Health Authority, GBA, the Federal Joint Committee in Germany has decided against the acceptance of this agent because it does not accept event-free survival (EFS) as a patient-relevant endpoint. So it's interesting that we have an agent that is now going to be FDA-approved. It's already FDA-approved and available in the United States, but it will not be at least available in Germany and there may be other countries that decide favorably or unfavorably depending on how this OS data is viewed.   So pivoting to another LAG-3 inhibitor in this case fianlimab, we're going to discuss Abstract 9501. So Abstract 9501 essentially is describing a phase II trial that evaluated the LAG-3 inhibitor, fianlimab, along with the anti-PD-1 inhibitor, cemiplimab from Regeneron. The data is slightly different from what we have seen with RELATIVITY-047, the Opdualag combination. So Jason, how would you contextualize the fian-cemi combination in advanced melanoma in the context of what we've seen with RELATIVITY-047? If you could help us with that, please. Dr. Jason Luke: Yeah, absolutely. So before we dive into this specific abstract, it's, like you mentioned, probably useful to just put all of this in context. Targeting LAG-3 as an immunomodulatory approach has actually been in clinic for a decade approximately. And so the relatlimab phase 1 started quite a long time ago. And there was data for nivolumab and relatlimab in PD-1 refractory patients with melanoma that showed not a tremendously obvious level of activity. And so it was thought there that the only place they would see that activity was to go to a frontline randomized phase 2 and then phase 3 trial, as we just discussed.  In contrast to that, given all the data that had come forward about LAG-3 targeting with relatlimab, the group developing fianlimab took a different approach and rather treated a cohort of patients with treatment-naive melanoma to try to get an initial assessment right away of the activity as read out by overall response rate for this PD-1 plus LAG-3 combination, which is cemiplamab plus fianlimab.   And these authors have previously presented data about this combination from cohorts of patients who are treatment-naive who received this combination and described approximately a 64% overall response rate. And that's an impressive number in the treatment-naive setting. There's sort of a tension there to sort of say, well, wait a minute, the response rate in this single-arm study is 64%, but in RELATIVITY-047, the response rate was lower for the LAG-3 combination and I think that's not a fair comparison. We have to realize this is a much smaller group of patients that has the potential to have been somewhat biased towards a better cohort just because of where and when they were recruited to participate in this trial. All the same, I think that number does look impressive and suggest that this combination is active in the frontline.   Specific to this abstract, though, what the authors presented here was to update those previous data and then specifically also to focus on a cohort of patients who are allowed to have had previous treatment in the perioperative setting. So either neoadjuvant or adjuvant therapies. And in a subgroup of patients, they observed that even in the patients that had received adjuvant anti-PD-1 who went on to then progress later, they got actually a similar overall response rate at approximately 60% even in that group. And so I think that that seems like an exciting number as well. One would on first principles think that if patients got an adjuvant anti-PD-1, then a PD-1 LAG-3 combo could be less active. When and how the patients progressed or did not on that adjuvant therapy, however, I think makes a big difference. And given the relatively small sample size of patients that were included in this report, which is on the order of 20-ish patients who were in the previous PD-1 treated adjuvant cohort, I don't know that we can make super broad analyses trying to compare across the development programs.  What I would take from this abstract, however, is that it does appear that this other PD-1 LAG-3 combination cemiplamab plus fianlimab is also very active and certainly deserves to be investigated in similar clinical trial contexts as the nivolumab plus relatlimab combination that we previously discussed. And while it's not specifically stated here, that is happening, there is a frontline phase 3 trial for this combination of fianlimab and cemiplamab as well as adjuvant considerations, also ongoing. Dr. Diwakar Davar: So, thank you. We've seen a lot of LAG-3 data this last 2 months, the phase 2/3a RELATIVITY-020 trial has just been published in the JCO, I encourage people to read that. And so that was the evaluation of nivolumab and relatlimabin the post-PD-1 patient population that Jason alluded to, where the response rate that was observed was 12%. So we've seen a lot of interesting data, a lot of interesting survival data, and now a new potential combination with LAG-3 with fianlimab and cemiplamab from Regeneron. So it'll be a very interesting next couple of years as we see whether or not this new combination, how it shakes up against the established nivu-rela combination, again, albeit with the limitations of cross-trial comparisons and also how it performs against cemiplamab in this ongoing, as you alluded to, ongoing global phase 3 trial.  So, pivoting away from melanoma, now addressing the context of another cutaneous malignancy, a very high-risk one, Merkel cell carcinoma. So, Merkel cell carcinoma for those who are not necessarily treating a lot of this is a very rare and very aggressive cutaneous tumor. It's a neuroendocrine tumor of the skin. It's a cancer that's typically associated more than about 60% of the time with a cancer-causing virus, an oncogenic virus known as a Merkel Cell Polyomavirus.   And in this setting, checkpoint inhibitor therapy has been approved for the last couple of years, initially with a PDL-1 inhibitor, avelumab, and then more recently with a PD-1 inhibitor, pembrolizumab. And, at this point in time, there are three FDA-approved agents that are checkpoint inhibitors that are available for the treatment of this disease.   And CheckMate-358 was essentially a trial of nivolumab plus/minus ipilimumab in the setting of this Merkel cell carcinoma. So, Jason, what are your thoughts on how the addition of ipi did in this setting [in Abstract 9506]?  Dr. Jason Luke: Yeah, so I think this is a really interesting abstract because there's a slightly more context even than what you alluded to there. This study is an open-label, multi-cohort, but single-arm investigation where one cohort of patients received nivolumab alone and the other cohort received ipilimumab. It needs to be buttressed by a previous publication in The Lancet last year by the group at the Moffitt Cancer Center who also did a prospective study looking at nivolumab and ipilimumab. In that previous study that the Moffit group did, they got a response rate of 100%. All patients responded to the combination of nivolumab and ipilimumab in their study and that was quite provocative, suggesting that while anti-PD-1 alone has about a 50% response rate, adding ipi in that scenario then took it to 100. So these data were very much of interest because this could be a confirmatory data set to suggest for this rare tumor that perhaps a combination regimen should be preferred. Of course, one has to remember that adding ipilimumab to anti-PD-1 substantially enhances the toxicity profile. And these patients tend to be elderly that develop this kind of cancer, Merkel cell carcinoma. So that's a rather important caveat.   Just to get to the crux of what happened in this trial. As opposed to the previous Moffit trial, there actually did not appear to be a major increase in the benefit of adding ipilimumab, at least in this trial. Because again, in parallel cohorts, the NIVO monotherapy arm had a 60% response rate, which is roughly a little bit higher, but roughly in line with what we've seen previously. And the response rate to nivolumab plus ipilimumab was 58%. So, I mean basically the same. So, how can it be then, that we have this previous very high-profile publication that says 100% response? Now, we have a second publication that says adding ipi doesn't do anything - that's confusing, and I think it'll be really important to try to look at what were the differences between these two cohorts of patients. Did one of them have higher risk features, greater disease burden, et cetera? We don't really know that just yet, but trying to tease that out will be important.  This data also emphasized, though, the complexity around the dosing of ipilimumab. And in melanoma, we never really figured out what the best dose of ipilimumab was to give either alone or even in combination with a PD-1. And we don't really have time to get into all of it right away here, but there are multiple studies in melanoma that would suggest that giving ipi on an every 3-week dosing schedule is superior to giving it on a 6-week dosing schedule. In this study, they did use the 6-week dosing schedule. So, whether or not that could have made a difference, I guess, is unknown. But I would notice that in the previous Moffitt trial, they also used that six-week dosing schedule. This one's a head-scratcher for why did these data not confirm a previous data set? But for the time being, I think this emphasizes that PD-1 monotherapy really is the standard approach that should be considered for patients with metastatic Merkel cell carcinoma.  Dr. Diwakar Davar: That's great, Jason. And so, again, it's a very tough patient population. These are very rare patients. The Moffitt trial that Jason alluded to essentially was a trial that had in each arm, there were approximately 25 patients, of which 13, or between 11 to 13 patients were actually checkpoint inhibitor naive, wherein the dramatic 100% response rate was seen. And this is a trial where at least in this update, we've got about 25 patients in nivo monotherapy, I mean in 43 patients. And so, in a disease that is thought to be extraordinarily sensitive to checkpoint inhibitor immunotherapy because of the role of the virus and the high TMB that it's associated with, it is very interesting that the addition of an additional checkpoint inhibitor did not appear to improve outcomes. But as you alluded to multiple reasons, but we don't know how it's going to shake out. Next, Abstract 9507 and this is a very interesting trial known as the MATISSE trial. So, in the context of cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma is a relatively not uncommon cancer, primarily seen in older cancer patients, particularly a little bit more common in men. And in this setting, we've got checkpoint inhibitor therapy that is FDA-approved, at least two of which are FDA-approved right now, pembrolizumab and cemiplamab both were approved in the advanced cancer setting. And we do know that because of the extraordinarily high tumor mutation burden associated with cutaneous squamous cell carcinoma, checkpoint inhibitor therapy has got a very dramatic effect. Response rates are between 35% to 42% with pembrolizumab and 40% to 50% with cemiplamab, depending on whether or not one looks at the relapsed metastatic or the locally advanced patient populations.  And interestingly, much like we've seen with melanoma, we have migrated the use of this therapy early in the lines of patients, particularly in the setting of perioperative therapy. So, Jason, how would you contextualize the results of the MATISSE trial in relation to the existing and known data from several of our colleagues regarding the role of what checkpoint inhibitor therapy is doing in terms of organ preservation?  Dr. Jason Luke: Yeah, and I think this is an area of tremendous excitement. And as you were alluding to, the activity of anti-PD-1 really was transformative in this disease, which really can be a disfiguring and locally destructive disease. And with that activity for unresectable disease, last year, near the end of the year, there was a first report of a large neo-adjuvant clinical trial in cutaneous squamous which showed really outstanding results in terms of improving surgery and pathologic complete response using anti-PD-1 in that setting. And for this trial, this was a trial done in Europe; they took a similar tact of trying to think about giving anti-PD-1 or anti-PD-1 with anti-CTLA-4 with ipilimumab in that neoadjuvant period to see whether or not they could reduce the use of extensive surgery and/or radiation therapy.  The short version is they were able to do that. And so they described 40% of patients with single-agent anti-PD-1 and 53% of patients who received a combination having major pathologic response to treatment. And this was so much so that 10 of the patients who had pathologic responses actually withdrew their consent to go on to have surgery because they decided that they had had such a good effect of the immunotherapy, they weren't willing to put themselves through what was going to be a very difficult surgery. And I think that speaks to the upside potential of these checkpoint immunotherapy approaches in certain settings, specifically here in cutaneous squamous cell carcinoma. Moreover, they describe clinical response in neoadjuvant setting as 50% for PD-1 monotherapy and 61% for the combination and I really think that this is really ready for prime time.  With the study published in the New England Journal last year and these data now, I really think the field needs to start moving towards the use of perioperative anti-PD-1 with or without ipilimumab as a standard approach. And I think it's the case that even the NCCN and ASCO and various guideline societies are going to start acknowledging that this ought to be considered for most patients who are facing difficult surgical operations for continuous squamous cell carcinoma. Dr. Diwakar Davar: So, Jason, you bring up a fascinating point, which is the appearance of this in guidelines. So this is undoubtedly extraordinarily good data. It's confirmatory, the pathologic response rates in many ways paradoxically low. You'd expect something about 50% or so. But the reason it's low is because 10% of patients who actually benefited didn't undergo surgery. So really the degree of benefit is tremendous. It's about 50% to 60%. So the fascinating thing in the setting that we'd have is if one is going to try to get the drug FDA-approved, what we now have is the conventional setting in which one needs a definitive endpoint. And at least we know that pathological response rate is not a definitive endpoint in the context of melanoma or, for that matter, cutaneous squamous cell carcinoma. The only setting in which it is a regulatory endpoint is a non-small cell lung cancer or triple-negative breast cancer. But recently there's been some very exciting data from another PD-1 inhibitor called dostarlimab in a trial done by your former colleague Dr. Luis Diaz when he demonstrated a dramatic result of dostarlimab in the context of perioperative rectal cancer where it is micro-satellite high wherein the standard of care is typically very disfiguring abdominal perineal resection.    So in the context of some of our listeners who might be thinking a little bit about how this pertains to regulatory approval, what are your thoughts about the paradigm of avoiding highly disfiguring surgery relating to what was seen in the rectal cancer discussion to what we're now seeing with perioperative therapy in the context of cutaneous squamous cell carcinoma?  Dr. Jason Luke: I think it's a very important question. And the easy out for diseases that have a pattern of progression that is metastasis is to use event-free survival which can include both the pre-surgical and the post-surgical period in terms of looking for whether or not the cancer comes back. And that works for diseases potentially like lung cancer, like you said, maybe melanoma. In cutaneous squamous cell carcinoma, however, that's not probably going to work because this tends to be a locally invasive and less of a metastatic disease. So here then, we really need to have sort of organization across patient advocacy, dermatology, medical oncology to come up with what the most appropriate considerations are going to be for evaluating that long-term benefit because I think we need a tangible result that we can show the FDA. Everyone is really impressed by these results, and I think that next step is to craft this into a way that we have a measurable output that we can then go to them with and say bless this so that all of our patients can get this kind of treatment. Dr. Diwakar Davar: Really great discussion, Jason. And I think this is going to be an area of particular interest going forward, given both the number of trials that have been conducted in this space and also the role of the very interesting regulatory paradigm that has now been set initially at least with the rectal cancer that is microsatellite high and now potentially we will see with cutaneous squamous cell carcinoma.   And so the final abstract that we have selected for you is Abstract 9511. And this is a trial that was conducted by a mutual colleague, Dr. Ryan Sullivan, and his colleagues. And it's essentially a trial of looking at targeted therapy with or without navitoclax in BRAF mutant melanoma patients. And part of the reason to highlight this, it's very interesting preclinical data supporting the addition of navitoclax, b but also a great example of an early trial that came through the CTEP portfolio. And so Jason, can you tell us about why this is exciting and how we might contextualize the addition of navitoclax to the targeted therapy backbone?   Dr. Jason Luke: Sure. So listeners will be quite aware of targeting mutant BRAF as a therapeutic strategy across oncology that was really initially pioneered in melanoma with the development of vemurafenib as the first selective BRAF inhibitor. But the field, of course, moved eventually to BRAF and MEK combinations across essentially all settings. We know that dabrafenib and trametinib are now approved pan-cancer for anywhere we find a BRAF V600e mutation. In the context of melanoma, looking at mechanisms of resistance, we observed that they were quite heterogeneous with reactivation of elements of the mitogen-activated protein kinase pathway, the MAPK pathway. But also there were metabolic changes in the cancer cells themselves which could drive resistance and were downstream of some of those reactivation signaling points. So one of those is the induction of anti-apoptotic machinery in the cell. So activation of BCL-2 or Bcl-xL to try to save those melanoma cells when they were under stress by blockade with BRAF and MEK inhibitors. And that observation was made now about a decade ago or more. And that raised the possibility that repurposing a drug that was being used actually in the chemo malignancy space might be useful in augmenting targeted therapy. And that's where we come in with the navitoclax as a BH3-mimetic that can actually knock down those antiapoptotic proteins, BCL-2 Bcl-xL. And so that was the context for this initially phase I clinical trial of combining navitoclax with the dabrafenib and trametinib.  And those data supported the safety of doing that and moved to this study, which was a randomized phase 2 study of that triplet regiment versus the dabrafenib and trametinib alone. And so this study started quite a long time ago, before the sort of initiation or widespread use of anti-PD-1 antibodies. And so it had to kind of undergo some various iterations throughout its course but eventually has now read out. And it had two primary endpoints, with one being focused on improving the complete response rate for targeted therapy because that's been associated with long-term outcomes as well as to look at the maximum tumor shrinkage of patients within this trial and of course to look at other endpoints like response rate, progression-free survival, et cetera.  About half the patients who participated in the trial had prior immune checkpoint blockade and they were actually distributed evenly across the two arms. So we think that probably won't impact on the outcomes. And what was observed in the clinical trial was that in fact, the triplet did improve the complete response rate for targeted therapy. So navitoclax plus dabrafenib and trametinib had a complete response rate of 20% versus dabrafenib and trametinib alone being at 15%. Both of them had an overall response rate in the 80% range, with slightly higher for the triplet at 84% versus 80% for the double-edged standard therapy. There was also a suggestion that there may be a disproportionate benefit for the triplet actually in patients with smaller baseline tumors. And we know that the efficacy of targeted therapy is more pronounced in the lower-volume disease state.   And so overall, when we look at this without really adding much toxicity, I think this is an intriguing place to look at further drug development. BRAF and MEK inhibition has been a backbone therapy in Melanoma for a long time, but we really haven't been able to move past it or augment it in any real way because of the heterogeneity of treatment resistance. And here, by going after metabolic changes, we perhaps might have the opportunity to enhance our targeted therapy somewhat further. And so we'll look forward to further results investigating this regimen in subsequent clinical trials. Dr. Diwakar Davar: Fantastic discussion, Jason. So these are all great insights. As you've heard, we've now discussed a couple of key abstracts covering major topics that will be presented, major themes of the malignancy space at ASCO 2023, including the addition of a lactate inhibitor to checkpoint in both a randomized large phase 3 trial and a smaller phase 2 trial, the context of targeted-therapy in melanoma making another forerun in the post-3c setting. And two very interesting studies I have looked at, checkpoint inhibitor therapy in the context of cutaneous squamous cell carcinoma and Merkel cell carcinoma, addressing themes that are of huge importance going forward, including the role of perioperative therapy in squam and the addition of a CTLA-4 inhibitor in Merkel. These oral abstracts are all going to be presented at the 2023 ASCO Annual Meeting. We look forward to seeing you there.  So, thank you Jason for taking the time to join us and for highlighting these important advances in immunotherapy. And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And finally, 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 podcast. Thank you for your attention. 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.   Follow today's speakers: Dr. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.02.535249v1?rss=1 Authors: Pemberton, J. M., Osterlund, E. J., Schoormann, W., Pogmore, J., Nguyen, D., Leber, B., Andrews, D. Abstract: Anti-apoptotic proteins such as BCL-XL promote cell survival by sequestering pro-apoptotic BCL-2 family members, an activity that frequently contributes to tumorigenesis. Thus, the development of small-molecule inhibitors for anti-apoptotic proteins, termed BH3-mimetics, is revolutionizing how we treat cancer. BH3 mimetics kill cells by displacing sequestered pro-apoptotic proteins to initiate tumor-cell death. Recent evidence has demonstrated that in live cells the BH3-only proteins PUMA and BIM resist displacement by BH3-mimetics, while others like tBID do not. Analysis of the molecular mechanism by which PUMA resists BH3-mimetic mediated displacement from full-length anti-apoptotic proteins (BCL-XL, BCL-2, BCL-W and MCL-1) reveals that both the BH3-motif and a novel binding site within the carboxyl-terminal sequence (CTS) of PUMA contribute to binding. Together these sequences bind to anti-apoptotic proteins, which effectively "double-bolt locks" the proteins to resist BH3-mimetic displacement. The pro-apoptotic protein BIM has also been shown to double-bolt lock to anti-apoptotic proteins however, the novel binding sequence in PUMA is unrelated to that in the CTS of BIM and functions independent of PUMA binding to membranes. Moreover, contrary to previous reports, we find that when exogenously expressed, the CTS of PUMA directs the protein primarily to the endoplasmic reticulum (ER) rather than mitochondria and that residues I175 and P180 within the CTS are required for both ER localization and BH3-mimetic resistance. Understanding how PUMA resists BH3-mimetic displacement will be useful in designing more efficacious small-molecule inhibitors of anti-apoptotic BCL-2 proteins. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.31.534530v1?rss=1 Authors: Sun, X.-M., Miles, G. J., Craxton, A., Powley, I. R., Galavotti, S., Chernova, T., Dawson, A., Nakas, A., Willis, A. E., Cain, K., MacFarlane, M. Abstract: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure and highly resistant to chemotherapy, potentially due to upregulated expression of the pro-survival proteins, BCL2/BCL-XL/MCL-1. Using clinically-relevant models of MPM we show that patient-derived primary MPM cell lines and ex-vivo 3D tumour explants are highly resistant to apoptosis induced by the BCL2/BCL-XL inhibitor, ABT-737. Importantly, we discover that 2-deoxyglucose (2DG), a glycolytic inhibitor, can sensitize MPM cells to ABT-737 and show this correlates with loss of the pro-survival protein, MCL-1. siRNA knockdown of MCL-1 (MCL-1 KD) combined with ABT-737 induced BAX/BAK-dependent, but BIM/PUMA-independent apoptosis, mimicking 2DG/ABT-737 treatment. MCL-1 KD/ABT-737 induced mitochondrial cytochrome c release and caspase-independent inhibition of mitochondrial respiration. Moreover, we observed a hitherto unreported caspase-dependent cleavage of glycolytic enzymes and subsequent inhibition of glycolysis. 2DG inhibited ERK/STAT3 activity, decreased MCL-1 mRNA and protein levels, with concurrent activation of AKT, which limited loss of MCL-1 protein. However, co-treatment with a specific AKT inhibitor, AZD5363, and 2DG/ABT-737 potently induced cell death and inhibited clonogenic cell survival, while in MPM 3D tumour explants MCL-1 protein expression decreased significantly following 2DG or 2DG/AZD5363 treatment. Notably, a similar synergy was observed in MPM cell lines and MPM 3D tumour explants using ABT-737 in combination with the recently developed MCL-1 inhibitor, S63845. Importantly, our study provides a mechanistic explanation for the chemoresistance of MPM and highlights how this can be overcome by a combination of metabolic reprogramming and/or simultaneous targeting of MCL-1 and BCL-2/BCL-XL using BH3-mimetics. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Featuring perspectives from Dr Srdan Verstovsek, including the following topics: Overview of current issues in the management of myeloproliferative neoplasms (MPN) (0:00) Treatment strategies for patients with myelofibrosis (MF) progressing after ruxolitinib (14:46) Correlation of molecular characterization and response to ruxolitinib in patients with MF (23:57) Rationale for and efficacy with combined inhibition of Bcl-2 and Bcl-xL for MPN (44:38)   Targeting calreticulin mutations for MPN (52:02) Advances in the management of polycythemia vera (57:54)  Developments in the care of patients with essential thrombocythemia (1:04:43)  Future directions in the clinical care of patients with MPN (1:12:46) CME information and select publications

Growing evidence fruit may lower type 2 diabetes risk Research has found eating at least two serves of fruit daily has been linked with 36% lower odds of developing type 2 diabetes Edith Cowan University (Australia), June 2, 2021 Eating at least two serves of fruit daily has been linked with 36 percent lower odds of developing type 2 diabetes, a new Edith Cowan University (ECU) study has found.  The study, published today in the Journal of Clinical Endocrinology and Metabolism, revealed that people who ate at least two serves of fruit per day had higher measures of insulin sensitivity than those who ate less than half a serve.  Type 2 diabetes is a growing public health concern with an estimated 451 million people worldwide living with the condition. A further 374 million people are at increased risk of developing type 2 diabetes. The study's lead author, Dr Nicola Bondonno from ECU's Institute for Nutrition Research, said the findings offer fresh evidence for the health benefits of fruit.  "We found an association between fruit intake and markers of insulin sensitivity, suggesting that people who consumed more fruit had to produce less insulin to lower their blood glucose levels," said Dr Bondonno.  "This is important because high levels of circulating insulin (hyperinsulinemia) can damage blood vessels and are related not only to diabetes, but also to high blood pressure, obesity, and heart disease. "A healthy diet and lifestyle, which includes the consumption of whole fruits, is a great strategy to lower your risk of developing type 2 diabetes." Fresh is best The study examined data from 7,675 Australians participating in the Baker Heart and Diabetes Institute's AusDiab Study and assessed fruit and fruit juice intake and the prevalence of diabetes after five years. Dr Bondonno said they did not observe the same beneficial relationship for fruit juice.  "Higher insulin sensitivity and a lower risk of diabetes was only observed for people who consumed whole fruit, not fruit juice," she said.  "This is likely because juice tends to be much higher in sugar and lower in fibre."  Dr Bondonno said that it's still unclear exactly how fruit contributes to insulin sensitivity, but it is likely to be multifaceted.  "As well as being high in vitamins and minerals, fruits are a great source of phytochemicals which may increase insulin sensitivity, and fibre which helps regulate the release of sugar into the blood and also helps people feel fuller for longer," she said. "Furthermore, most fruits typically have a low glycaemic index, which means the fruit's sugar is digested and absorbed into the body more slowly."  The study builds on Dr Bondonno's research into the health benefits of fruit and vegetables, particularly those that contain a key nutrient known as flavonoids. The research is part of ECU's Institute of Nutrition Research.     Ginkgo biloba leaves have multicomponent and multitarget synergistic effects on treatment of neurodegenerative diseases Jiangsu Kanion Pharmaceutical Co (China), June 1, 2021 According to news reporting out of Jiangsu, People's Republic of China, research stated, “Ginkgo biloba L. leaves (GBLs), as widely used plant extract sources, significantly improve cognitive, learning and memory function in patients with dementia. However, few studies have been conducted on the specific mechanism of Neurodegenerative diseases (NDs).” Our news journalists obtained a quote from the research from Jiangsu Kanion Pharmaceutical Co. Ltd., “In this study, network pharmacology was employed to elucidate potential mechanism of GBLs in the treatment of NDs. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to obtain the chemical components in accordance with the screening principles of oral availability and drug-like property. Potential targets of GBLs were integrated with disease targets, and intersection targets were exactly the potential action targets of GBLs for treating NDs; these key targets were enriched and analyzed by the protein protein interaction (PPI) analysis and molecular docking verification. Key genes were ultimately used to find the biological pathway and explain the therapeutic mechanism by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Twenty-seven active components of GBLs may affect biological processes such as oxidative reactions and activate transcription factor activities. These components may also affect 120 metabolic pathways, such as the PI3K/AKT pathway, by regulating 147 targets, including AKT1, ALB, HSP90AA1, PTGS2, MMP9, EGFR and APP. By using the software iGEMDOCK, the main target proteins were found to bind well to the main active components of GBLs.” According to the news editors, the research concluded: “GBLs have the characteristics of multi-component and multi-target synergistic effect on the treatment of NDs, which preliminarily predicted its possible molecular mechanism of action, and provided the basis for the follow-up study.” This research has been peer-reviewed.     Diets that promote inflammation could increase breast cancer risk Analysis of dietary patterns for over 350,000 women suggests eating more anti-inflammatory foods helps lower risk Catalan Institute of Oncology and Biomedical Research Institute (Spain) June 7, 2021  A new study of more than 350,000 women found that women with diets incorporating more foods that increase inflammation in the body had a 12% increase in their risk of breast cancer compared to women who consume more anti-inflammatory diets. The new findings are being presented at NUTRITION 2021 LIVE ONLINE.  The study authors found that moving from a more anti-inflammatory diet toward one that increases inflammation upped breast cancer risk in an almost linear manner. Foods that increase inflammation include red and processed meat; high-fat foods such as butter, margarines and frying fats; and sweets including sugar, honey and foods high in sugar. Fruits, vegetables, legumes, tea and coffee all have potentially anti-inflammatory properties. "Most studies examining diet and breast cancer risk have focused on single nutrients or foods rather than the whole diet," said the study's first author Carlota Castro-Espin, a predoctoral fellow at the Catalan Institute of Oncology and Bellvitge Biomedical Research Institute in Barcelona, Spain. "People consume food not nutrients, thus examining overall dietary patterns, rather than single components of diets can lead to more accurate conclusions when analysing associations with a health outcome such as breast cancer."  The new results are based on data from the European Investigation into Cancer and Nutrition (EPIC) study, a prospective study that recruited more than 500,000 participants across 10 European countries starting in the mid-1990s. The study included more than 13,000 breast cancer diagnoses during approximately 15 years of follow-up.  The typical diet for EPIC participants was measured for a year using food frequency or diet history questionnaires. The researchers used this information to calculate an inflammatory score for each study participant based on their intake of 27 foods.  The researchers examined dietary patterns linked with inflammation because long-term, low grade inflammation has been linked with the development of breast cancer. The large number of women in the study allowed the researchers to take a more nuanced look at the relationship between dietary patterns and breast cancer risk.  Their analysis showed that the increase in breast cancer risk due to pro-inflammatory diets appears to be more pronounced among premenopausal women. They also found that the association did not vary by breast cancer hormone receptor subtypes.  "Our results add more evidence of the role that dietary patterns play in the prevention of breast cancer," said Castro-Espin. "With further confirmation, these findings could help inform dietary recommendations aimed at lowering cancer risk."  As a next step, the researchers plan to evaluate the association of the inflammatory potential of diet and other dietary patterns with breast cancer survival using participants in the EPIC study.      Emerging impact of quercetin in the treatment of prostate cancer Shahid Beheshti University of Medical Sciences (Iran), June 3, 2021   According to news originating from Tehran, Iran, research stated, “Quercetin is a flavonoid agent detected in fruits and vegetables with anti-inflammatory, antioxidant, and anticancer effects. This flavonoid can suppress cell cycle transition and induce apoptosis in neoplastic cells.” Our news reporters obtained a quote from the research from Shahid Beheshti University of Medical Sciences: “Therapeutic effects of quercetin have been assessed in diverse cancers including prostate cancer through the establishment of in vitro and in vivo experiments. Moreover, this agent might prevent the initiation of this type of cancer as it indirectly blocks the activity of promoters of two important genes in the pathogenesis of prostate cancer i.e. androgen receptor (AR) and prostate specific antigen (PSA). Several in vitro investigations have identified the differential influence of quercetin on normal prostate cells versus neoplastic cells, emphasizing its specific cytotoxic effects on cancerous cells. The most appreciated route of quercetin effect on prostate cancer cells is the detachment of Bax from Bcl-xL and the stimulation of caspase families. Besides, quercetin might enhance the effects of other therapeutic options against prostate cancer. For instance, a combination of TNF-related apoptosis-inducing ligand (TRAIL) and quercetin has been recommended as a novel modality for the treatment of prostate cancer.” According to the news editors, the research concluded: “These kinds of strategies might overcome resistance to apoptosis in cancer cells. In the current paper, we summarize the recent data about the preventive and therapeutic influences of quercetin in prostate cancer.”     Breast microbiome modified by diet, fish oil Wake Forest School of Medicine, June 4 2021.    Findings reported on June 3, 2021 in Cancer Research add evidence to the effects of diet on the breast's microbiome, the community of microorganisms that exists in breast tissue.  “We have recently demonstrated that dietary patterns modulate mammary microbiota populations,” wrote David R. Soto-Pantoja and colleagues. “An important and largely open question is whether the microbiome of the gut and mammary gland mediates the dietary effects on breast cancer.” To help answer this question, the researchers fed a high fat or a control diet to mice that are susceptible to developing breast cancer. Animals that received the high fat diet had a greater number of tumors, more rapid tumor growth and larger tumor size than those that received the control diet.  Next, mice that were given high fat diets received fecal transplants from mice that received control diets, and control diet-fed animals received transplants from high fat diet-fed animals. The team found that animals that received the control diet developed as many tumors as mice that received the high fat diet.   In a double-blind trial, breast cancer patients were given fish oil supplements or a placebo for two to four weeks prior to surgical removal of their tumors. The researchers observed a change in the microbiota of tumor and normal breast tissue in participants who received fish oil, including an increase in Lactobacilli (which has been associated with reduce breast cancer tumor growth in animals) in normal tumor-adjacent breast tissue of participants who received fish oil for four weeks.  "Obesity, typically associated with a high-fat diet consumption, is a well-known risk factor in postmenopausal breast cancer," commented coauthor Katherine L. Cook, PhD, of Wake Forest University. "This study provides additional evidence that diet plays a critical role in shaping the gut and breast microbiome."     Self-administered aroma foot massage may reduce symptoms of anxiety   Okayama University (Japan), June 8, 2021  Researchers at Okayama University conduct the first community-based study on the effects of self-administered aromatherapy foot massage on stress and anxiety symptoms. The results suggest aromatherapy massages might provide an inexpensive, simple way of managing anxiety.   The continuing popularity of complementary therapies, such as aromatherapy and massage, has prompted scientists to investigate the effects of such therapies on the body in more detail. Complementary therapies are said to reduce the symptoms associated with stress and anxiety, and therefore may reduce the chances of severe illness, such as hypertension and heart disease. The precise effects on the body following such therapies is unclear, however.   Previous studies have focused on the effects of massage and aromatherapy treatments on blood pressure and mental state in hospitalized patients in Japan, but none have been conducted on individuals living in the community. Now, Eri Eguchi and co-workers at Okayama University, together with researchers across Japan, have conducted the first study into the effect of aromatherapy-based foot massage on blood pressure, anxiety and health-related quality of life in people living in the community.   57 participants took part in the study; 52 women and 5 men. Baseline blood pressure and heart rate values were taken at the start and end of the four-week trial period, as well as at a follow-up session 8 weeks later. Participants also completed questionnaires on anxiety status and health-related quality of life at each stage of the trial. The participants were divided into two groups, and one group were taught to perform a 45-minute aromatherapy-based foot massage on themselves three times a week for four weeks.   The results suggest that aroma foot massage decreased the participants' average blood pressure readings, and state of anxiety, and tended to increased mental health-related quality of life score. However the effect of massages was not significant with changes in other factors such as physical health-related quality of life scores and heart rate.   In their paper published in March 2016 in PLOS One, Eguchi's team are cautiously optimistic about the potential for self-administered massage to reduce anxiety in the population: "[although] it was difficult to differentiate the effects of the aromatherapy from the effects of the massage therapy... [the combination] may be an effective way to increase mental health and improve blood pressure."     Aromatherapy and massage Aromatherapy has long been used to relieve stress and anxiety in populations across the globe. Different aroma essential oils are said to have different properties, and are used to induce relaxation and promote well-being. Trials have indicated that certain essential oils, when inhaled, can reduce blood pressure levels and alleviate depression by stimulating the olfactory system. Massage (in its many forms) also has a long history in therapeutic medicine, and the practice of manipulating key pressure points in the body to induce relaxation has been shown to improve mental and physical health. However, detailed scientific studies of the effects of aromatherapy foot massage – an increasingly popular treatment in Japan – on blood pressure and perceived quality of life are limited.   Significance and further work While the trial carried out by Eguchi and her team is limited in some respects, their results provide an initial starting point from which to extend studies into the benefits of aroma foot massage for the general population. Their findings that massage, or the aromatherapy, or a combination of both, reduce blood pressurereadings (at least in the short term) warrants further investigation. Eguchi and her team acknowledge that their decision to advertise for participants may have encouraged more health-conscious and pro-active people to apply. They also received far more applications from women than men, although their age-range (from 27 to 72) was diverse. Further work is needed to determine the effect of aroma foot massage on specific age and sex categories, for example, before such interventions are encouraged in the wider population.     Proteomics reveals how exercise increases the efficiency of muscle energy production University of Copenhagen (Denmark), May 27, 2021 Mitochondria are the cell's power plants and produce the majority of a cell's energy needs through an electrochemical process called electron transport chain coupled to another process known as oxidative phosphorylation. A number of different proteins in mitochondria facilitate these processes, but it's not fully understood how these proteins are arranged inside mitochondria and the factors that can influence their arrangement. Now, scientists at the University of Copenhagen have used state-of-the-art proteomics technology to shine new light on how mitochondrial proteins gather into electron transport chain complexes, and further into so-called supercomplexes. The research, which is published in Cell Reports, also examined how this process is influenced by exercise training.  "This study has allowed for a comprehensive quantification of electron transport chain proteins within supercomplexes and how they respond to exercise training. These data have implications for how exercise improves the efficiency of energy production in muscle," says Associate Professor Atul S. Deshmukh from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.  Traditional methods provide too little detail It is already well established that exercise training stimulates mitochondrial mass and affects the formation of supercomplexes, which allows mitochondria in skeletal muscle to produce energy more efficiently. But questions remain about which complexes cluster into supercomplexes and how. To better understand supercomplex formation, particularly in response to exercise, the team of scientists studied two groups of mice. One group was active, and given an exercise wheel for 25 days, and the second group was sedentary, and was not provided the exercise wheel. After 25 days, they measured the mitochondrial proteins in skeletal muscle from both groups to see how the supercomplexes had changed over time.  When scientists typically analyze how supercomplexes form, they use antibodies to measure one or two proteins per electron transport chain complex. But as there can be up to 44 proteins in a complex, this method is both time consuming and provides limited information about what happens to the remainder of the proteins in each complex.  As a result, there is a lack of detailed knowledge in the field. Proteomics helps supercomplexes give up their secrets To generate much more detailed data, the team applied a proteomic technology called mass spectrometry to measure the mitochondrial proteins. By applying proteomics instead of antibodies, the scientists were able to measure nearly all of the proteins in each complex. This provided unprecedented detail of mitochondrial supercomplexes in skeletal muscle and how exercise training influences their formation. Their approach demonstrated that not all of the proteins in each complex or a supercomplex respond to exercise in the same manner.  "Mitochondrial protein content is known to increase with exercise, thus understanding how these proteins assemble into supercomplexes is crucial to decipher how they work. Our research represents a valuable and precious resource for the scientific community, especially for those studying how the mitochondrial proteins organize to be better at what they do best: produce energy under demand,", explains Postdoc Alba Gonzalez-Franquesa. The interdisciplinary project was a collaboration between the Deshmukh, Treebak and Zierath Groups at CBMR, and the Mann Group at the Novo Nordisk Foundation Center for Protein Research.

Dr Strasser talks to ecancertv at ASH 2013. Impaired apoptosis is considered one of the prerequisites for the development of most, if not all, cancers, but the mechanisms that guarantee the sustained survival of most cancer cells remain unknown. Members of the Bcl-2 family are key regulators of apoptosis and include proteins essential for cell survival and those required to initiate cell death. Studies with transgenic mice have shown that over-expression of Bcl-2 or related pro-survival family proteins, such as Bcl-xL or Mcl-1, can promote tumorigenesis, particularly in conjunction with mutations that deregulate cell cycle control, such as deregulated c-myc expression. It is, however, not known whether expression of pro-survival Bcl-2 family members under endogenous control is required to maintain the survival of cells undergoing neoplastic transformation. Using Eµ-myc transgenic mice, a well-characterized model of human Burkitt’s lymphoma, we investigated the role of endogenous Bcl-2 in lymphoma development. Bcl-2 was found to be dispensable for the development of Eµ-myc pre-B/B lymphoma. In contrast, loss of Bcl-xL and even, more remarkable, loss of a single allele of Mcl1 greatly impaired lymphoma development. Experiments with inducible knockout mice demonstrated that Mcl-1 but not Bcl-xL is essential for the sustained survival and expansion of Myc-driven malignant pore-B/B lymphoma. Remarkably, even loss of one Mcl1allele greatly impaired lymphoma growth. These findings were translated into using lymphoid malignancies by using inducible expression of selective antagonists of distinct pro-survival Bcl-2 family members. Such studies showed that Mcl-1 is also critical for the sustained survival and expansion of Burkitt Lymphoma, a Myc-driven malignancy. These observations indicate that (even relatively weak) targeting of Mcl-1 may be an attractive strategy.

Introduction: Sepsis is still a leading cause of morbidity and mortality, even in modern times, and thrombocytopenia has been closely associated with unfavorable disease outcome. Decreases in mitochondrial membrane potential (depolarization) were found in different tissues during sepsis. Previous work suggests that mitochondrial dysfunction of platelets correlates with clinical disease activity in sepsis. However, platelet mitochondrial membrane potential (Mmp) has not been investigated in a clinical follow-up design and not with regard to disease outcome. Methods: In this study, platelet mitochondrial membrane depolarization was assessed by means of a fluorescent Mmp-Index with flow cytometry in 26 patients with sepsis compared with control patients. Platelet Mmp-Index on admission was correlated with the clinical disease scores Acute Physiology and Chronic Health Evaluation Score II (APACHE II), Sequential Organ Failure Score (SOFA), and Simplified Acute Physiology Score II (SAPS II). Finally, platelet Mmp-Index on admission and follow-up were compared in the group of sepsis survivors and nonsurvivors. Expression of the prosurvival protein Bcl-xL in platelets was quantified by immunoblotting. Results: Platelet mitochondrial membrane depolarization correlated significantly with the simultaneously assessed clinical disease severity by APACHE II (r = -0.867; P < 0.0001), SOFA (r = -0.857; P < 0.0001), and SAPS II score (r = -0.839; P < 0.0001). Patients with severe sepsis showed a significant reduction in platelet Mmp-Index compared with sepsis without organ failure (0.18 (0.12 to 0.25) versus 0.79 (0.49 to 0.85), P < 0.0006) or with the control group (0.18 (0.12 to 0.25) versus 0.89 (0.68 to 1.00), P < 0.0001). Platelet Mmp-Index remained persistently low in sepsis nonsurvivors (0.269 (0.230 to 0.305)), whereas we observed recovery of platelet Mmp-Index in the survivor group (0.9 (0.713 to 1.017)). Furthermore, the level of prosurvival protein Bcl-xL decreased in platelets during severe sepsis. Conclusion: In this study, we demonstrated that mitochondrial membrane depolarization in platelets correlates with clinical disease severity in patients with sepsis during the disease course and may be a valuable adjunct parameter to aid in the assessment of disease severity, risk stratification, and clinical outcome.

Melanoma is an often fatal form of skin cancer which is remarkably resistant against radio- and chemotherapy. Even new strategies that target RAS/RAF signaling and display unprecedented efficacy are characterized by resistance mechanisms. The targeting of survival pathways would be an attractive alternative strategy, if tumor-specific cell death can be achieved. Bcl-2 proteins play a central role in regulating survival of tumor cells. In this study, we systematically investigated the relevance of antiapoptotic Bcl-2 proteins, i.e., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1, in melanoma cell lines and non-malignant cells using RNAi. We found that melanoma cells required the presence of specific antiapoptotic Bcl-2 proteins: Inhibition of Mcl-1 and A1 strongly induced cell death in some melanoma cell lines, whereas non-malignant cells, i.e., primary human fibroblasts or keratinocytes were not affected. This specific sensitivity of melanoma cells was further enhanced by the combined inhibition of Mcl-1 and A1 and resulted in 60% to 80% cell death in all melanoma cell lines tested. This treatment was successfully combined with chemotherapy, which killed a substantial proportion of cells that survived Mcl-1 and A1 inhibition. Together, these results identify antiapoptotic proteins on which specifically melanoma cells rely on and, thus, provide a basis for the development of new Bcl-2 protein-targeting therapies.

Introduction Currently available treatments for osteoarthritis (OA) are restricted to nonsteroidal anti-inflammatory drugs, which exhibit numerous side effects and are only temporarily effective. Thus novel, safe and more efficacious anti-inflammatory agents are needed for OA. Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the NF-kappa B signalling pathway. Methods We have recently demonstrated that in chondrocytes resveratrol modulates the NF-kappa B pathway by inhibiting the proteasome, while curcumin modulates the activation of NF-kappa B by inhibiting upstream kinases (Akt). However, the combinational effects of these compounds in chondrocytes has not been studied and/or compared with their individual effects. The aim of this study was to investigate the potential synergistic effects of curcumin and resveratrol on IL-1 beta-stimulated human chondrocytes in vitro using immunoblotting and electron microscopy. Results Treatment with curcumin and resveratrol suppressed NF-kappa B-regulated gene products involved in inflammation (cyclooxygenase-2, matrix metalloproteinase (MMP)-3, MMP-9, vascular endothelial growth factor), inhibited apoptosis (Bcl-2, Bcl-xL, and TNF-alpha receptor-associated factor 1) and prevented activation of caspase-3. IL-1 beta-induced NF-kappa B activation was suppressed directly by cocktails of curcumin and resveratrol through inhibition of I kappa kappa and proteasome activation, inhibition of I kappa B alpha phosphorylation and degradation, and inhibition of nuclear translocation of NF-kappa B. The modulatory effects of curcumin and resveratrol on IL-1 beta-induced expression of cartilage specific matrix and proinflammatory enzymes were mediated in part by the cartilage-specific transcription factor Sox-9. Conclusions We propose that combining these natural compounds may be a useful strategy in OA therapy as compared with separate treatment with each individual compound.

The study is subdivided into two different parts: the first part deals with the development of a method to gain uterus milk in vivo during the preimplantation periode in cattle for the investigation of regulatory factors. The second part investigates different proteases in bovine follicles 20 hours after GnRH (Gonadotropin releasing hormone) injection (shortly bevor ovulation) for comparable as well as in the corpus luteum (CL) during oestrous cycle and induced luteolysis. In addition apoptotic as well as anti-apoptotic factors were evaluated in the CL during oestrous cycle and induced luteolysis. For the development of a method for gaining uterus milk in vivo during the first 24 days of gravidity in cattle, nine heifers were cycle synchronised using the Ovsynch method and artificially inseminated. Before flushing an epiduralanaesthesia was given and both uterus horns were flushed with 13ml 0.9% NaCl using a balloon embryo transfer catheter at day 5, 7, 12, 17 and 24 of gravidity. The catheter was placed 1cm cranial to the bifurcatio uteri in both horns. It was possible to retrive between 3ml and 13ml of the used flushing fluid. The uterus milk from the ipsilateral horn was inspected for an embryo and an EDTA-stabilisator was given to the uterus milk of both horns. An infection of the uterus occured in three heifers after the second and in five heifers after the third flushing. In one heifer no infection was found. Between day 17 and day 24 all heifers showed clear signs of oestrus. It was possible to detect progesterone, oestradiol-17-beta, PGF2alpha and VEGF via enzyme immunoassay (EIA) and radio immunoassay (RIA), respectively. Because of the occurred infection no statistic analysis was made. But it could be seen that the level of progesterone ranged between

Der programmierte Zelltod (Apoptose), ist ein evolutiv konserviertes Selbstmordprogramm der Zelle, um auf äußere oder endogene Signale zu reagieren. Es dient dazu, überflüssige und/oder geschädigte Zellen zu entfernen. Dieser Prozess ist bei Krankheiten wie z.B. Krebs teilweise außer Kraft gesetzt, und bei Parkinson- oder Alzheimer-Erkrankung zu stark ausgeprägt. Im Rahmen dieser Arbeit wurden zwei Gene biochemisch und molekularbiologisch näher charakterisiert. Bei diesen zwei Genen, die mit Hilfe eines speziell zur Identifikation dominanter, Apoptose–induzierender Gene entwickelten Screnningsverfahrens identifiziert wurden, handelt es sich um CybL, eine Komponente von Komplex II der Atmungskette, und um Saip (Small apoptosis inducing protein) einem Protein, das am endoplasmatischen Retikulum (ER) lokalisiert ist. Bisher war bekannt, daß die Atmungskettenkomplexe I und III bei der Fas-Ligand und der Ceramid-vermittelten Apoptose beteiligt sind. Über einen Zusammenhang von Komplex II und Apoptose-Induktion war zu Beginn dieser Arbeit nichts beschrieben. Im Rahmen dieser Arbeit wurde entdeckt, daß neben CybL kann auch noch die kleine Untereinheit von Komplex II (CybS) Apoptose auslösen kann, wohingegen die übrigen Komponenten von Komplex II, das Flavinprotein (FAD) und das Eisen–Schwefelprotein (FeS), nicht in der Lage sind, Apoptose zu induzieren. Die laut Datenbank vorhergesagten vier Transmembrandomänen von CybL sind für die apoptoseinduzierende Eigenschaft notwendig. Darüber hinaus führt nur eine 3,8–fache Induktion von CybL über dem endogenen CybL zu Apoptose in Säugetierzellen. In der vorliegenden Arbeit konnte auch gezeigt werden, daß CybL einerseits bei Überexpression Apoptose induzieren kann, und andererseits Apoptose durch seine Inaktivierung reduziert wird. Daß CybL damit ein spezifischer Sensor für Apoptose ist, konnte dadurch ermittelt werden, daß eine Reihe verschiedener Apoptosestimuli (Doxorubicin, Etoposid, Menadion, Cisplatin, Taxol) und der Fas-Rezeptor einen intakten Komplex II zur Signalvermittlung benötigen. Dazu wurde mit sogenannten B9/B30 Zellen gearbeitet. B9/B30-Zellen sind Lungenfibroblasten aus Hamsterzellen, in denen CybL inaktiv ist (B9), wohingegen die B30-Zellen ein Fusionsprotein zwischen CybL und GFP enthalten, welches die physiologische Aktivität von Komplex II wiederherstellt. In den B9-Zellen ist die Apoptoseinduktion durch Cytostatika (Ausnahme Arsentrioxid) bzw. durch den Fas-Rezeptor reduziert, verglichen mit den B30-Zellen. Auch Untersuchungen an HeLa WT- bzw. HeLa 0-Zellen (die keine intakte Atmungskette besitzen) zeigten, daß für die Apoptoseinduktion mit den oben genannten Reagenzien eine intakte Atmungskette benötigt wird. Im Jahre 2000 wurde CybL als Tumosupressor beschrieben. Es ist daher zu vermuten, daß die Tumorsuppressor-Eigenschaften von CybL auf der Fähigkeit von Komplex II beruhen, proapoptotische Signale aufzunehmen und weiterleiten zu können. Bisher war bekannt, daß eine transiente Inhibition einiger Atmungskettenkomplexe (Komplex I, II, III) zur Bildung von reaktiven Sauerstoffintermediaten (ROI) führt. Es konnte gezeigt werden, daß auch CybL bei Überexpression reaktive Sauerstoffintermediate produziert, und daß viele proapoptotische Signale zur spezifischen Inhibition von Komplex II führt. Da bereits eine geringe Expression von CybL ausreichend ist, um Komplex II zu inhibieren, und dadurch Apoptose ausgelöst wird, kann Komplex II als spezifischer Sensor für Apoptose angesehen werden. Das bisher unbekannte Gen mit dem Namen Saip löst dominant Apoptose in Säugetierzellen aus. Die proapoptotische Eigenschaft von Saip ist vermutlich auf einen evolutiv konservierten Mechanismus zurückzuführen, da auch ein Homolog aus C.elegans nach transienter Transfektion in Säugerzellen Apoptose auslöst. Dabei induziert Saip Caspase-abhängige Apoptosewege, die zur Apoptose-typischen DNA–Fragmentierung und Bildung von apoptotischen Körperchen (Membran blebbing) führt. Es konnte auch eine physikalische Protein-Proteininteraktion (mittels Co-Immunpräzipitation) mit Bap31 gefunden werden. Dieses Protein ist ebenfalls am ER lokalisiert und Bestandteil eines lokalen Apoptose-Sensors, der einen Proteinkomplex mit Procaspase-8L sowie antiapoptotischen Mitgliedern der Bcl-2-Familie (Bcl-2 bzw. Bcl-XL) bildet. Des weiteren interagiert Saip auch mit einer Deletionsmutante von Spike (Small protein with inherent killing effect-SpikeN19), einem neuen proapoptotischen BH3-only Protein, das ebenfalls am ER lokalisiert ist, und an Bap31 bindet. Saip ist ein ubiquitäres Protein und wird in sehr vielen der getesteten Gewebe und Zelltypen exprimiert. Im Northern-Blot-Verfahren konnte vergleichsweise eine hohe Expression an humaner Saip-mRNA in Niere, Placenta, Herz, Leber, Dünndarm und Skelettmuskulatur detektiert werden. Mit Hilfe von weiteren Northern-Blots wurde herausgefunden, daß Saip durch diverse Reagenzien, die bekanntermaßen Apoptose induzieren können, transkriptionell hochreguliert wird. So ist zum Beispiel das Signal von Saip nach 5-Fluorouracil-Behandlung (5FU), um das 80-fache gegenüber der Kontrolle erhöht. 5FU ist ein sehr effektives und bekanntes Zytostatikum, das in der Klinik zur Behandlung von Colon- und Mammakarzinomen erfolgreich eingesetzt wird. Wird Saip mittels der RNAi–Methode deaktiviert, wird die 5FU-induzierte Apoptose um 1/3 reduziert. Saip könnte somit eine wichtige Rolle in der Behandlung von Tumoren spielen, die mit 5FU therapiert werden.

During my PhD thesis I was working on the identification of novel apoptosis-inducing genes by using a novel genetic expression screen (Grimm and Leder, 1997). One of the identified genes turned out to be a evolutionary conserved cDNA that codes for a novel BH3-only protein of 219 amino acid residues which was named Spike, for Small protein with inherent killing effect. Spike was then in the course of my PhD thesis extensively characterised, molecularly and biochemically. In summary, upon overexpression in mammalian cells Spike efficiently leads to all features of apoptosis, such as phenotypic alterations, cytochrome c release, caspase activation and DNA degradation. It was shown that Spike localised to the endoplasmic reticulum, where it interacts with a recently identified apoptosis regulating protein complex, consisting of Bap31, Bcl-2, Bcl-XL and an ER-specific isoform of caspase-8: pro-caspase 8L (Breckenridge et al. 2002). Although no direct interaction with anti-apoptotic members of the Bcl2-family could be observed, the importance of the BH3-like sequence for the apoptosis-inducing activity of Spike was demonstrated by using point mutations of conserved amino acid residues of this motif (Mund et al. 2003). Instead of directly interacting with anti-apoptotic members of the Bcl-2 family Spike is able to interfere with the complex formation between Bap31 and Bcl-XL. Based on these data I proposed a model according to which the complex on Bap31 is controlled by Bcl-2/Bcl-XL as long as they are associated. Displacement of Bcl-2/Bcl-XL from Bap31 by Spike leads to the formation of a pro-apoptotic complex. In addition, Spike appears to be implicated in the cell death signal of the Fas receptor. I observed that a dominant-negative version of Spike and a highly effective anti-sense oligonucleotide significantly reduced Fas-mediated DNA fragmentation whereas no reduction was detected in TNFa-induced cell death (Mund et al. 2003).