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Addressing Questions & Unmet Needs in Melanoma Research and Treatment
- 1. Unanswered Questions and Unmet Needs in Melanoma Research and Treatment Dr. Marc Hurlbert, Chief Science Officer, Melanoma Research Alliance Dr. Tom Williams, Manager, Project Management, Elsevier Tuesday 19th May 2020
- 2. Agenda • Melanoma Epidemiology & Pathophysiology • Melanoma Research Alliance • MRA Current Scientific Priorities • Melanoma Insights & Analytics • Review of Current Treatments • Rare Melanomas and Unmet Needs • Future Directions
- 3. Melanoma Epidemiology & Pathophysiology • >100,000 new cases of invasive melanoma in US in 2020 • And nearly 8,000 deaths in 2020 • Melanoma <5% of skin cancer cases • Greatest incidence of melanoma is in Australia, Northern Europe, and North America • Lowest incidence in South America, Africa, and South Asia • prevalence in US doubled between 1982- 2011, and steadily increasing • Melanoma-related deaths starting to decline due to changes in sun exposure, screenings, and treatment improvements
- 4. Melanoma Epidemiology & Pathophysiology • Lifetime risk for developing melanoma: − 1 in 1000 for African Americans − 1 in 200 for Latin Americans − 1 in 50 for Caucasians • 5-year survival outcome (estimated % of cancer patients who will not have died from melanoma five years after diagnosis): Rates based on US data − 98% in localized melanoma cases − 64% in regional melanoma (stage IIII) cases − ~23 % in cases with distant metastases • Survival rates lower in elderly populations; 10% differences between under 45-year age group and the 75+ age group
- 5. Background on Melanoma Research Alliance • Founded in 2007 by Debra and Leon Black with the help of Michael Milken • Mission: to end suffering and death due to melanoma by collaborating with all stakeholders to accelerate powerful research, advance cures for all patients, and prevent more melanomas. • MRA is the largest nonprofit funder of melanoma research and awarded $123 million to 339 research programs at 152 institutions in the US and 18 countries
- 6. Melanoma Research Funding Landscape Direct Research Funding (based on ICRP database) CY2006 CY2015 Latest CY estimate National Institutes of Health (NIH/NCI) $ 96,879,147 $ 175,547,174 $ 192,000,000** Melanoma Research Alliance (MRA) $ - $ 11,117,365 $ 12,402,645‡ Department of Defense (CDMRP) $ - $ 2,494,745 $ 10,900,000‡ UK National Cancer Research Institute (coalition of 22 funding organizations, including CRUK) $ 4,234,024 $ 11,117,516 $ 7,029,000** French National Cancer Institute (INCa) $ - $ 1,181,586 $ 3,459,000** Canadian Cancer Research Alliance (coalition of 34) $ 4,205,007 $ 3,146,975 $ 3,327,000* Dutch Cancer Society (KWF) $ 79,734 $ 2,256,809 $ 3,018,000‡ Melanoma Research Foundation (MRF)*** $ 350,000 $ $1,300,000 $ $1,530,000† American Cancer Society (ACS) $ 3,200,879 $ 2,437,900 $ 1,229,000† Cancer Australia $ - $ 676,152 $ 512,122** Grand Total (estimates) $ 109,217,000 $ 211,075,000 $ 240,000,000 2016*,2018**,2019†, 2020‡ ***MRF data estimated from MRF website; not a component of the ICRP database (www.icrpartnership.org) Manuscript submitted, Trends in International Cancer Research 2006-2015, JCO Global Oncology
- 7. MRA Research Portfolio ($123M since 2007) • Hallmarks of MRA research portfolio include a focus on developing new treatments (89%) • A smaller portion supports melanoma research related to prevention/etiology (5.1%) or diagnosis/staging (5.5%) • Treatments research projects include molecular targets (n=139), immunotherapy (n=134), or combinations (n=23) Prevention/Etiology, 5.14% Diagnosis/Staging, 5.46% Treatment, 89.40%
- 8. MRA Grant Award Mechanisms Team Research: requires multidisciplinary teams and involvement of a Young Investigator. $900k and up over 3-years Established Investigator: past their first four years of faculty appointment with an established record of scientific productivity. $375k over 3-years Young Investigator: within four years of first faculty appointment, requires a mentorship commitment from a senior investigator. $225k over 3-years Pilot: test potentially transformative ideas that may not have extensive data, but articulate a clear hypothesis – “high-risk, high-reward.” $100k over 2-years Dermatology Fellow: engaging clinical dermatologists in melanoma research, requires mentorship and fellowship in Dermatology Department. $35k for 1-year; year 2 possible
- 9. MRA Grant Solicitation & Selection Process • Release Annual Request for Proposals (RFP) – includes Special Emphasis Areas, Special Opportunities • Grants Reviewed by standing Grant Review Committee: https://www.curemelanoma.org/about-mra/grant-review-committee/ Current chairs: Marcus Bosenberg and Caroline Robert • In-person Grant Review Committee meeting • Slate of grants approved by MRA Board of Directors
- 10. EIA, 17.22% AIP, 3.40% Pilot, 2.44% TSA, 59.73% YIA, 16.95% Derm Fellows, 0.26% MRA Awards by Mechanism ($123M since 2007) • MRA offers awards for interdisciplinary teams and individual investigators • 339 awards have been granted since 2007 • Focus on collaborative, team science: Team Science Awards (TSA), which fund multidisciplinary research groups, account for 60% of research funding to date • Individual investigator awards: Established Investigator (EIA), Young Investigator (YIA), Pilot/Development Awards, Dermatology Fellows (Derm) and Academic- Industry Partnership Awards (AIP) • Emphasis on Young Investigators: The YIA program is another centerpiece of the MRA strategy, MRA has supported a total of 176 Young Investigators to date
- 11. MRA Current Scientific Priorities • Identifying strategies to overcome treatment resistance, difficult-to-treat melanoma subtypes such as acral, mucosal, or uveal melanoma, and/or non-BRAF-mutant melanomas such as NRAS or NF1-mutant; • Informing logical and optimal combination therapies, therapeutic sequences, and/or treatment regimens in adjuvant and neoadjuvant approaches; • Developing strategies to prevent and/or treat metastatic disease; • Identifying markers of response, resistance, and/or risk of recurrence or death; • Improving prevention and early detection strategies; and/or developing new diagnostic approaches, including artificial intelligence or machine-learning endeavors.
- 12. Immunotherapy Top Trend in Melanoma Protein Targets Research Most studied targets involved in autophagy, immune response, cell development, cell differentiation, cell function, cell growth, cell migration, cell phenotype, cell survival, and tumor growth. 1. BRAF regulates cell proliferation, differentiation & survival. − BRAF is an oncogene, and mutations involved in 60– 70% of cases. 2. PDCD1 negatively regulates immune response. − PD-1 expressed in 10-60% of melanomas − Not until 2011 did publications emerge relating to melanoma. − Exponentially increase year on year, and now PDCD1 overtaken BRAF as the number one target protein Queried Resnet, Elsevier’s Biological Database for protein targets and melanoma
- 13. Small Molecules and Targeted Therapeutics in Melanoma Pipeline From 2008–2009: − 18 small molecule drugs marketed − 48 small molecule drugs in pre-clinical or clinical phases − 23 discontinued small molecules, and one withdrawn − majority of drugs approved were inhibitors of kinases, growth factors, members of cytochrome P450 family, and histone deacetylases. From 2018–2019: − 39 small molecule drugs marketed − 41 small molecule drugs in pre-clinical or clinical phases − 14 discontinued small molecules − Targeting the same as 2008-2009 but a significant increase in drugs targeting mutant proteins e.g. BRAF V600E mutations, EGFR receptor carrying the L858R mutation. Move to focus on targeted therapeutics toward patients with specific melanoma gene mutations.
- 14. Genetic predisposition & cancer driver mutations linked to melanoma 23 genes shown to be linked to hereditary melanoma: • 12 genes have 177 genetic variants linked to melanoma • 11 genes genetically linked to melanoma that currently have no known genetic variants associated with melanoma Research Gap: a) map genetic variants, b) are they clinically significant, c) do they impact gene function 752 genes genetically linked to sporadic melanoma and its subtypes: • 449 genetically linked variants to sporadic melanoma and its subtypes. Research Gap: 54 variants are not currently genetically linked to any known melanoma gene 24 genetic variations predisposing to melanoma influence the response to 39 melanoma drugs: • Studies with Temsirolimus and melanoma cells proved ineffective, combination therapy was more effective. However, studies in specific populations is lacking • e.g. rs121434592 gene variant + treatment temsirolimus, these patients had longer progression free survival. Currently in phase III clinical trials as a treatment for several cancers, and if successfully approved it could warrant investigation into treatment of melanoma patients carrying the AKT E17K mutation. = E17K mutation genetic variant
- 15. Melanoma, immune suppression & gaps in melanoma treatment • 226 melanoma cell surface secreted/expressed proteins capable of inhibiting activation of the immune system. • 142 melanoma cell surface secreted/expressed proteins that can activate immune tolerance; • = 368 potential mechanisms that melanoma cells can inhibit immune response. To develop personalized immunotherapies, molecular profiling of a melanoma biopsy must be performed to determine the exact immunosuppression mechanism.
- 16. Melanoma Trending Topic • In 2018, 2/3 of most cited research papers with melanoma in the title, abstract, or keywords discussed the influence of the microbiome on the response to melanoma treatment in humans. • Significant growth in research Including implication of microbiota in: − onset and progression of cancers − toxicity and the response rate of cancer treatments. • The link between melanoma and microbiome trending due to the recent findings that response to immune checkpoint inhibitors correlates with the composition, diversity, and functional differences in patients’ microbiomes.
- 17. Melanoma Trending Topic • Increase in research for predictors of therapeutic response beyond the tumor by focusing on host factors, such as microbiota and host genomics. • Microbiota is a modifiable factor, and potentially can become not just a predictive marker but also a potential target in order to improve outcomes for melanoma patients. • Since 2018, four clinical trials are registered to look at modulating the gut microbiome’s impact on response to immunotherapy of melanoma at clinicaltrials.gov and are currently recruiting patients or about to start the recruitment.
- 18. Current Molecularly Targeted Therapies • First BRAF inhibitor (vemurafenib) for BRAF mutant advanced melanoma approved in 2011 • First combination BRAF (dabrafenib)+MEK (trametinib) inhibitors for BRAF mutant advanced melanoma approved in 2013 • Second combination BRAF+MEK inhibitors (vemurafenib+cobimetinib) approved in 2014 • Third combination BRAF+MEK inhibitors (encorafenib+binimetinib) approved in 2018 • More recent approvals in adjuvant setting after surgery for stage III and surgically resectable stage IV Image from: Ahmed et al., SHP2 drives adaptive resistance to ERK signaling inhibition in molecularly defined subsets of ERK-dependent tumors, Cell Reports 2019 Jan;26(1):65-78
- 19. Current Immunotherapies • Immune checkpoint inhibitors have revolutionized the treatment of advanced melanoma • First anti-CTLA4 inhibitor (ipilimumab) was approved in 2011 • First anti-PD1 inhibitors ((pembrolizumab) nivolumab) approved in 2014 • Nivolumab in combination with ipilimumab for unresectable or metastatic melanoma approved in 2016 • First oncolytic virus (talimogene laherparepvec, T-vec) for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that recurred after initial surgery approved in 2015 Image adapted from Dr. Jedd Wolchock, Memorial Sloan Kettering Cancer Center, New York, NY
- 20. Emerging Immunotherapies • Numerous other immune checkpoint inhibitors are being tested in preclinical models and clinical trials • Approaches to improve immunotherapy by targeting other components of the tumor- immune-microenvironment are being studied • Targeting dendritic cells, tumor associated macrophages and other immune cells are being exploredImage adapted from Dr. Padmanee Sharma, University of Texas MD Anderson Cancer Center, Houston, TX
- 21. Microbiome in Melanoma • Thomas Gajewski, University of Chicago, TSA 2013, Molecular mechanisms of T cell inflamed melanoma to identify new targets • Yardena Samuels, Weizmann Institute of Science, TSA 2016, Identifying somatic and microbial neo-antigens associated with melanoma responses • Thomas Gajewski, University of Chicago, TSA 2018, Commensal microbiota and anti-PD-1 efficacy • Lorenzo Cohen and Jennifer Wargo, TSA 2018, University of Texas MD Anderson Cancer Center, Diet, Mental Health, and the Microbiome in Response to Immunotherapy • Simon Heidegger, Technical University of Munich, BMS-MRA YIA 2019, Microbial metabolites in immunotherapy of malignant melanoma
- 22. Rare Melanomas and Unmet Needs • Rare melanomas may have a different etiology than cutaneous melanoma, including fewer with BRAF mutations • Acral melanoma occurs on the palms, soles of feet, and nail beds, with approximately 5000 new US cases each year • Mucosal melanoma invades the mucosal tissue including nasal cavity, sinuses and mouth, GI tract, vagina, anus and other areas in the body, with approximately 1000 new US cases each year • Uveal melanoma, or melanoma of the eye, has approximately 2500 new US cases each year • Improved diagnostics and treatments are needed for rare melanomas Images from MRA website (www.curemelanoma.org)
- 23. Future Directions • Understanding why some patients respond while other patients do not respond to current therapies − Understanding innate and acquired resistance to current therapies • Developing AI/machine learning to improve melanoma detection, diagnostics and prognostics • Understanding, preventing and treating melanoma metastasis • Exploring the role of the microbiome in melanoma • Understanding the etiology of rare melanomas and how best to diagnose and treat
- 24. How to get the Melanoma report C U S T O M R E P O R T I N G : The development of custom reports and analytics based on large, integrated sets of Elsevier data solutions, customer data, and/or externally published information. Disease areas & cancers Target-related custom reports General scientific opportunity analysis Animal translatability models …and more OTHER CUSTOM REPORTS INCLUDE
- 25. Who is the Professional Services team at Elsevier?
- 26. Questions & Contact us Email us at: Elsevier: t.williams@elsevier.com Melanoma Research Alliance: mhurlbert@curemelanoma.org
- 27. Thank you
Editor's Notes
- Hello everyone and welcome to today’s webinar Addressing Questions & Unmet Needs in Melanoma Research and Treatment. My name is Matthew Morton, Senior Marketing Manager for Elsevier’s Professional Services team, and I’ll be your moderator for today’s webinar.
- Matt Morton The melanoma research and treatment landscape has rapidly changed over the last decade. Since 2011, the FDA has approved 12 new melanoma treatment regimens – including new classes of drugs that are molecularly targeted therapies, immune checkpoint inhibitors, and other immunotherapies. This webinar will showcase key insights and analytics around Melanoma, treatment effectiveness and resistance trends, and what the future may hold regarding research and clinical advancements. I’m joined on this webinar by Dr. Marc Hurlbert, Chief Science Officer at the Melanoma Research Alliance and Dr. Tom Williams, Project Management Lead for Professional Services at Elsevier: Dr. Williams will be sharing high-level melanoma statistics, epidemiology and pathophysiology information, and other key insights and analytics around the disease. Dr. Hurlbert will then walk through the funding landscape, current and emerging molecularly targeted therapies and immunotherapies, and how the fight against other rare melanomas are keeping the Melanoma Research Alliance busy. Before I hand it over to Dr. Hurlbert and Dr. Williams, I would like to first share some brief housekeeping items. If you have any questions during the presentation, please submit them at any time through the question panel. We will address as many questions as we can at the end of the presentation. If we cannot get to your question, we will follow up via e-mail. If you are experiencing technical issues such as sound quality, first try logging out and logging back in. If issues persist, please e-mail help@brighttalk.com. You can refer to that e-mail address in the announcement panel below the presenter screen. They will be able to address your issues. With that said, I’d like to pass it off to Dr. Williams and Dr. Hurlbert.
- Melanoma is a tumor of melanocytes, which are the cells responsible for skin pigmentation and protection from UV radiation. It is most commonly cutaneous, but in rare cases may also affect the eye, the mucous membranes of the head and neck, the gastrointestinal tract, and the genital tract. And Marc is going to discuss this a little later on Malignant melanoma is an increasingly important global health problem. And it is predicted that over 100,000 new cases of invasive melanoma will arise and nearly 8,000 deaths in 2020 in the US However, it only accounts for less that 5% of skin cancer cases The prevalence in US has doubled between the early 80s to present day, and is steadily increasing, however, deaths relating to Melanoma are starting to decline and this is posited because of changes in sun exposure, screenings, and treatment improvements The Analytical Services team at Elsevier, determined the Disability Adjusted Life Years (which is referred to as the DALYs rate), and this is the sum of years of life lost and years lived with a disability, and it was calculated to be 22% for the melanoma global DALY rate, which results in melanoma being responsible for more than 20 years of life lost and years lived with disability worldwide per 100,000 people
- Patients are at a higher risk of developing melanoma if they: Family history of it Have Dys PLASTIC nevi Those with with a greater number of common nevi (ie, typical, benign) have Fair skin types or Light eye color And have are exposed to Intermittent intense sun exposure or long-term chronic exposure As you can see 1 in 1000 for African Americans 1 in 200 for Latin Americans 1 in 50 for Caucasians are at risk of developing melanoma during their life times However, survival rates are pretty high. The 5-year survival outcome is 98% in localized melanoma cases 64% in regional melanoma (stage IIII) cases ~23 % in cases with distant metastases But Survival rates are lower in elderly populations; and there is a 10% differences between under 45-year age group and the 75+ age group Prevention Behavioral interventions has a great impact on the rates of developing melanoma. Many of us know to Use sunscreen with a sun protection factor of 15 or more Wear sun-protective clothing Avoid midday sun Avoid sunburn Avoid tanning beds but behavioral changes are sometimes difficult to adopt I am not going to hand over to Marc to discuss the Melanoma Research Alliance and their funding initiatives
- Founded in 2007 by Debra and Leon Black, with the help of Michael Milken. You likely know Milken who founded the Prostate Cancer Foundation in the early 1990s and today leads the nonprofit Milken Institute. When Debra was diagnosed, after finishing treatment, Debra and Leon asked Michael what they could do to advance melanoma research. He encouraged them to found MRA and structure it to advance the world’s most promising research. At the time MRA was founded, it had been a decade since a treatment had been approved by the FDA. The available treatments were not effective in the majority of patients, and if melanoma became metastatic, outcomes were dismal in 2007. Since our founding, MRA has become the largest non-profit, non-governmental funded of melanoma research. $123 million to 339 research programs; at 152 unique research institutions Across the US and in 18 countries.
- Shown here is research grant funding data. The source is a shared-grants database called the International Cancer Research Partnerships (ICRP) which was formed in 2000 ICRP includes 136 funding organizations – NIH, DOD, nonprofits – from US, Canada, Europe, Asia and Australia All members code grants to a common ontology, Common Scientific Outline Database includes over $50-billion of peer-reviewed grant awards from 2000 to present The table in the slide shows melanoma-specific research funding in 2006 and 2015; a manuscript on cancer research funding has been submitted The last column shows the latest most recent calendar-year for which data is available by partner, primarily 2018, 2019.
- MRA has granted $123 million in competitive, peer-reviewed grant funding since 2007 The focus has been on research into the discovery, translation, and development of new treatments (89%) About 11% has been focused on research into prevention, early detection and diagnosis of melanoma Within the Treatment grants portfolio, included are research projects on signal transduction kinases (molecular targets), immunotherapy including immune-checkpoint (systemic) as well as localized, intratumoral / intralesional therapies; and combinations of therapies.
- Shown are the MRA Grant Award mechanisms. MRA’s annual Request for Proposals (RFP) is typically released every August, with proposals due in October/November timeframe. Visit MRA website at www.CureMelanoma.org and you can see our 2019 RFP You can add your name to our notification list to be contacted when future RFPs are released
- MRA utilizes an open- RFP process. Eligible institutions (academic, nonprofit) are able to apply from anywhere in the world. All proposals are reviewed in a competitive, peer-review process with each proposal examined by 2 or 3 independent reviewers, and then discussed among our Grant Review Committee All proposals recommended for funding are considered and must be approved by MRA Board of Directors
- Shown are the current Scientific Priorities as published in our 2019 Request for Proposals; The MRA priority areas shift every few years Sign-up at our website to receive our next RFP, which we intend to release in mid-August
- We analyzed the melanoma targets researched between 1987 and 2019. and it showed that the protein targets most studied are: B-Raf proto-oncogene serine/threonine kinase (BRAF), programmed cell death 1 (PDCD1), cyclin dependent kinase inhibitor 2A (CDKN2A), melanocyte inducing transcription factor (MITF), and interleukin 2 (IL2). And looking at the function of these it shows that they are involved in autophagy, immune response, cell development, differentiation, cell function, and growth, and migration, cell phenotype, cell survival, and tumor growth. And If we just take a closer look on just the data for BRAF and PDCD1 BRAF regulates cell proliferation, differentiation & survival. It is an oncogene, and mutations in this gene are involved in 60–70% of cases. PDCD1 it negatively regulates immune response. And it is expressed in 10-60% of melanomas What we see is an emerging trend, there were no publications related to the involvement of programmed cell death 1 in melanoma until 2011. The number of publications has exponentially increased year on year, and by 2018, programmed cell death 1 began to overtake BRAF as the number one target protein published in relation to melanoma And this further supporting the concept that immunotherapy is a top trend in current melanoma research.
- Next we looked at small molecules that have been developed to target melanoma: From 2008–2009: 18 small molecule drugs marketed 48 in pre-clinical or clinical phases 23 discontinued, and one withdrawn And the majority of drugs approved were inhibitors of kinases, growth factors, members of cytochrome P450 family, and histone deacetylases. From 2018–2019: There were 39 small molecule drugs marketed 41 in pre-clinical or clinical phases And 14 discontinued These were targeting the same as the 2008-2009 cohort but there is a significant increase in drugs targeting mutant proteins. Which again is showing how targeted therapies are becoming more prevalent Probably DON’T REVIEW The one small molecule that was discontinued was estradiol, which is the principal intracellular human estrogen. It was initially shown in studies to interact with both alpha- and beta-estrogen receptors, which play a role in promoting cell growth and cellular antiproliferation, respectively. In vitro and in vivo studies showed that estradiol resulted in inhibition of melanoma cell growth, elucidating a potential melanoma drug candidate. However, later studies showed that the inhibition of beta-estrogen receptor increased the risk for developing cutaneous melanoma and spread of metastatic cells, resulting in an increased risk of skin malignant melanoma. Now, due to these findings, melanoma patients with increased levels of endogenous estrogens during pregnancy, those taking oral contraceptives and hormone replacement therapies containing estradiol should be made aware of the potential increased risk of melanoma development or melanoma progression.
- There are still plenty research gaps in the melanoma space. Analysis of the genes linked to hereditary and sporadic melanoma reveal some of these gaps. If you look at the 23 genes that are linked to hereditary melanoma, 11 of these genes currently have no known genetic variants associated with melanoma Therefore looking to map genetic variants, determine if they are clinically significant, and whether they impact gene function is a gap that needs filling Of the 752 genes genetically linked to sporadic melanoma, 54 variants are not currently genetically linked to any known melanoma genes, again revealing a research opportunity. And another opportunity is the 24 genetic variants that influence treatment responses to 39 melanoma drugs If we take a look at TEM-si-Role-E-mus treatment, initially it appeared to be an ineffective treatment for melanoma in cell studies, in combination with other drugs there is increased efficacy. However what is lacking is particular studies for specific genetic variations Looking specifically at the AKT pathway, which is one of the most frequently activated pathways in cancer. And we then look at this Missense glutamate 17 Lysine mutation which has recently been reported to promote melanoma to brain metastasis, it shows as prior work has suggested that this mutation is associated with longer progression free survival response when treated with temsirolimus in endometrial carcinoma studies therefore it may be a good opportunity to look to see if melanoma could be a possible new indication for TEM-siRole-E-mus. Drug repurposing is an efficient way to help find new ways to treat diseases using other drugs developed for other indications.
- Another research opportunity is the influence of immune suppression and treatment: There are 386 potential mechanisms that melanoma cells can inhibit immune response And the development of personalized immunotherapies has to be thorough with the inclusion of molecular profiling of a melanoma biopsy to determine the exact immunosuppression mechanism. For example Because of potential ineffectiveness, certain drugs in SOME patients with immune responses suppressed by non-PDCD1 mechanisms, if you are treating with these drugs in Red, they may not show great results, but may need to be given in combination with non=PDCD1 immune suppressing drugs
- One of the interesting finds through our analytics was when we used Elsevier’s Text Mining for new trending terms that had a semantic relations with cancers. And it showed the emergence of the microbiota and microbiome as a big new trend We saw that In 2018, 2 out of 3 most cited research papers about melanoma discussed the influence of the microbiome on the response of melanoma treatment in humans. There is Significant growth in this area particularly related to the: onset and progression of cancers And toxicity and the response rate of cancer treatments. And this is trending because of the recent findings that response to immune checkpoint inhibitors correlates with the composition, diversity, and functional differences in patients’ microbiomes.
- And before I hand back over to Marc, We semantically looked for bacterial species in relation to immune checkpoint-related concepts Which showed an Increase in research for predictors of therapeutic response that focused on host factors. And because this is a modifiable factor, there is a new potential target to improve outcomes for melanoma patients. Which we see with the four clinical trials are registered
- About 50% of patients with cutaneous melanoma have tumors with BRAF mutations (BRAF V600E or other) RAF activation occurs in response to activation of RAS proteins by upstream growth factor-induced signals Activated RAF in turn phosphorylates and activates MEK1 and 2, which in turn phosphorylate and activate ERK1 and 2. The activation of this signaling cascade – the Classical MAP kinase pathway) regulates a number of effector kinases and transcription factors that drive key cellular processes, including cell proliferation Remarkable clinical activity with the RAF inhibitor (vemurafenib) in melanomas containing mutant BRAF was initially presented at ASCO 2009, only 7years after the discovery of BRAF mutations in human cancer (2002 Davies et al). Combinations; overcoming resistance
- Matt Morton Thank you Dr. Hurlbert and Dr. Williams for that great presentation. We hope we you enjoyed this deep dive into the Melanoma research and treatment landscape. As follow up, all webinar registrants will be receiving a complimentary copy of the Elsevier Melanoma report that was written and created by the Professional Services team. Reports like these are just one of many of its kind, as the types of information being analyzed and conveyed can vary by use case and utility. For example, some of these include reports around other disease areas and cancers, target-related custom reports, general scientific opportunity analysis, animal translatability models, and more.
- Matt Morton For additional context, Elsevier Professional Services is a team of consultants with backgrounds in data science, informatics, chemistry, pre-clinical research, and clinical development. The team provides data integration and applied analytics as standalone services and via Elsevier’s Entellect platform. As experts in scientific domains, industry-standard taxonomies, and custom content and data curation, the team addresses complex data challenges in the pharma biotech, life sciences, drug discovery, and other industries.
- Matt Morton Thank you all again for coming, we will now answer some questions. I see that there are a lot of questions in the panel, so we’ll only be able to answer a few of them. For those that we cannot answer, we will follow up via e-mail. (For Tom): You noted the possible exploration of drug repurposing in melanoma, could you comment on that further (for Marc): The microbiome was highlighted during the presentation. Can Dr. Hurlbert comment on MRA’s investments into the research on the microbiome related to melanoma? (for Marc): Given MRA’s leadership role as the largest nonprofit funder of melanoma research, what does MRA see as the most exciting or most challenging areas in melanoma research?
- Matt Morton I see that we’re out of time for today. Unfortunately, we weren’t able to answer all of the questions, but we will follow up with you via e-mail. I want to thank everyone again for attending today’s webinar on the melanoma research and treatment landscape. If you have any further questions or would like to inquire about Professional Services or the Melanoma Research Alliance, please email Dr. Williams or Dr. Hurlbert.