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The Society for Melanoma Research Newsletter Published By: The Society for Melanoma Research

Volume 31 | June 2019

Edited By: Marie Webster, Ph.D. & Rohit Thakur, Ph.D.

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SMR Congress provides the opportunity to present and/or view innovative data related to clinical and basic melanoma research. Deadline to Submit: July 29, 2019

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Important Reminder: Don’t forget to submit your nominations for the SMR Annual Awards

For more information on the SMR annual awards (Including past winners) visit the SMR website.

AWARD NOMINATIONS: SMR is seeking nominations for the 2019 Annual Awards. These awards will be presented at the 2019 Society for Melanoma Research Congress

Nominations are due July 29th, 2019

Click here to submit your nominations for the following awards:

  • Lifetime Achievement Award
  • Young Investigator Award
  • Outstanding Research Award

Click here to submit your nomination for the Christopher J. Marshall Award

Melanoma News

STEM for Women: Empowering Women in Melanoma Research

By: Rohit Thakur, Ph.D.

As a part of an initiative to empower women in melanoma research, we invited women to participate in interviews in which they were asked to share their experience and advice. The first set of these interviews were conducted at the Society for Melanoma Research Congress in Manchester England. The aim of this new initiative is to highlight the scientific contributions, career paths, as well as major challenges faced by women in STEM and strategies they have used to overcome these challenges. New interviews will be released as videos on the society’s website every month. We hope that you will join us in celebrating the achievements of women in melanoma research.

The third interview, which is currently on the SMR website is with Dr. Jennifer Wargo who runs a translational research laboratory at MD Anderson. During her career she has made important contributions toward our current understanding of melanoma from clinical, biological, and environmental perspectives. She is currently working on translating mechanistic findings, of the role of gut microbiome in response to immunotherapy, into the clinic to improve treatment outcome for melanoma patients.

Her “bedside to bench” and then “bench to bedside” approach has proved to be successful. She is a strong supporter of team science and believes that “we are stronger together and the best way to help our patients is by sharing data. The end game is to help patients”. As a result of her team science approach, three landmark studies linking gut microbiome to response to immunotherapy were published together [1-3]. For young scientists, she advises being open to new ideas, and pursuing inter-disciplinary research. She imagines the future as a brave new world of science, where translational researchers, clinicians, statisticians, nutritionists, biologists, immunologists, and funding agencies are working together to make informed decisions using big data ultimately to improve patient care.

  1. Gopalakrishnan, V., et al., Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science, 2018. 359(6371): p. 97-103.
  2. Routy, B., et al., Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science, 2018. 359(6371): p. 91-97.
  3. Matson, V., et al., The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science, 2018. 359(6371): p. 104-108.

FDA Holds Workshop Focused on Central Nervous System (CNS) Metastases

By: Michael Davies, MD, PhD, MD Anderson Cancer Center

Metastasis to the central nervous system (CNS) is one of the most common and devastating complications of advanced melanoma. CNS metastases have historically been one of the leading causes of death from melanoma, and the presence of CNS involvement portends a poor prognosis for patients. Indeed, the recent update of the American Joint Commission on Cancer (AJCC) staging manual for melanoma included a new, separate category (M1D) for stage IV patients with CNS involvement. Developing strategies to more effectively prevent and treat CNS metastases remains a key challenge in this disease. Indeed, the Melanoma Research Foundation has previously organized two workshops focused specifically on this problem, to facilitate and expedite research on CNS metastasis.(1, 2)

One critical challenge to improving outcomes for patients with CNS metastases is limited access to clinical trials. It is very common for clinical trials to exclude patients with active brain metastases or leptomeningeal disease. For example, the management and outcomes of patients with advanced melanoma has been revolutionized by the approval of 11 new immune and targeted therapy treatments since 2011. All of these agents were approved based on phase III clinical trials that compared new treatments versus the standard of care at that time. Importantly, every one of those key registration studies excluded patients with active CNS disease. While such patients have often been excluded due to concerns about penetration of agents into the CNS or unique toxicities, multiple post-approval trials that have been conducted with these agents in patients with brain metastases have demonstrated significant clinical activity. Further, the trials have confirmed similar incidence and patterns of toxicities as those previously reported in patients without CNS involvement. Together, the trials support the feasibility of including patients with CNS involvement in clinical trials, and question their common exclusion from investigational studies. Notably, this exclusion of patients with CNS metastases from clinical trials is common in most cancer types.

In recognition of the unmet need for more clinical trials for cancer patients with CNS involvement, the US Food and Drug Administration (FDA) and the National Brain Tumor Society (NBTS) co-sponsored a public workshop, “Product Development for Central Nervous System Metastases.” The meeting was organized in collaboration with several organizations, including the Melanoma Research Alliance (MRA), and was held on the FDA campus on March 22, 2019, with a concurrent live webcast to provide expanded access to the proceedings (1). The meeting had over 200 participants and audience members, which included FDA regulators, academic investigators, pharmaceutical industry representatives, patient advocacy groups, and patients. The meeting began with an introduction by Dr. Richard Pazdur, the Director of the FDA’s Oncology Center of Excellence (OCE), and was followed by sessions and panel discussions on multiple key topics, including current management strategies, clinical trial development, clinical trial endpoints, and basic and translational research needs in this field. Participants in the meeting from the melanoma field included Dr. Kim Margolin, Dr. Michael Davies, Dr. Hussein Tawbi, and Dr. Michael Atkins.

There was a strong consensus from the meeting, including from the FDA, to expand access of clinical trials, including early-phase investigations, to patients with CNS metastases based on the results of recent clinical trials. While formal meeting reports and recommendations are expected in the next few months, the FDA has released a draft guidance document relating to cancer clinical trial eligibility criteria on brain metastases, which is now publicly available (2). In addition, educational videos were prepared summarizing both standard and investigational treatments for brain metastases, which were made available to meeting participants prior to the workshop (3). These videos are in the process of being made publicly available through the NBTS website, and include presentations on Melanoma, Lung Cancer, Breast Cancer, Leptomeningeal Disease, and Radiation Therapy. The NBTS has also released key discussion points and messages from the meeting (Table 1) (4). In addition to recommendations regarding clinical trials, discussions at the meeting highlighted the development of more clinically relevant preclinical models, and more research into the pathogenesis and therapeutic resistance of CNS metastases, as critical unmet needs. There was also consensus that while there has been a notable increase in research and treatments focused on brain metastases, there remains very little investigation in the area of, or progress for, LMD.

Overall, the meeting demonstrated the need for continued advocacy for clinical, translational, and basic research focused on key challenges that must be overcome to improve outcomes for patients with CNS metastases. Importantly, the meeting reinforced the importance of this topic to the FDA and resulted in many positive conversations between academic and industry investigators about how to work together to expand early access to promising therapies and clinical trials. The meeting has already provided tools which should be useful to investigators, and hopefully will lead to additional impact through collaborative efforts across diseases to provide more treatment options for patients.

Table 1: Key Points and Action Items

  • There is enthusiasm for including patients with CNS metastases broadly in clinical trials, and having opportunities for all such patients is a major source of hope for them.
  • There is general consensus that these patients can be more broadly included in trials without compromising safety or trial design, and many past assumptions need to be challenged.
  • There is strong research identifying potential targets for drugs.
  • Additional guidance from FDA would be welcome.
  • There is recognition that more needs to be done to include in trials patients with leptomeningeal disease.
  • There is a need to develop trials and drugs that specifically target brain metastases.
  • Developing new innovative endpoints and selection of endpoints for trials involving brain metastases patients remains a major challenge, and ultimately might depend on the trial, drug, cohort of patients, and other specific facts. Appropriate endpoints may differ between early and late clinical development.
  • Imaging is one area where more work needs to be done to help make radiographic endpoints more feasible in trials with brain metastases patients. This will include refinement and adoption of RANO brain metastases guidelines, as well as the development of standards for acquiring imaging data in trials using new and advanced imaging methods.

https://braintumor.org/our-research/cns-metastases-workshop/

  1. Information available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-nbts-public-workshop-product-development-central-nervous-system-cns-metastases
  2. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM633132.pdf
  3. Currently available via: https://www.fda.gov/drugs/news-events-human-drugs/fda-nbts-public-workshop-product-development-central-nervous-system-cns-metastases
  4. Provided by David Arons, Chief Executive Officer, NBTS, on April 25, 2019

SMR Member News

Congratulations to Dr. Allison Betof Warner on starting her Assistant Professor position at Memorial Sloan Kettering in New York City where her lab will focus on melanoma research and exercise science. Congratulations also to Dr. Marie Webster for her new Assistant Professor position at the Lankenau Institute for Medical Research, where her lab will focus on melanoma research and epigenetic regulation of cell fate. We at SMR are so proud of our next generation!

Congratulations to Dr. Genevieve Boland (Massachusetts General Hospital), Dr. Srinivas Saladi (Massachusetts Eye and Ear Infirmary, and Dr. David Liu (Dana Farber Cancer Institute) for receiving the MRF Breakthrough Consortium Award Young Investigator Team Award to Advance the Field of Immuno-Oncology for our project titled: “Characterizing the Role of the Hippo Pathway During Melanoma Immunotherapy”! https://www.melanoma.org/research-center/scientific-initiatives/mrf-breakthrough-consortium

Congratulations to Dr. Daniela De Zio on receiving the Young Investigator Award from the Melanoma Research Alliance for her proposal entitled: “The multifaceted Ambra1-based signaling in melanoma response to therapy.

Congratulations to Dr. Penny Lovat, Dr. Daniela De Zio, and co-authors on acceptance of their paper entitled: “Epidermal AMBRA1 and Loricrin; a paradigm shift in the prognostication and stratification of AJCC stage I melanomas” for publication in The British Journal of Dermatology. For more information please click here.

Congratulations to Dr. Michael Davies on his appointment to Chair of Melanoma Medical Oncology at MD Anderson!

Congratulations to Dr. Viviana Vallacchi, Dr. Rivoltini Licia et al. on publishing their study entitled: “Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma” in the Journal of Clinical Investigation! In their study they identified a set of eight MDSC-miRNAs involved in regulation of MDSC function, that were upregulated in circulating CD14+ cells, and in tumor lesions from melanoma patients in association with myeloid cell infiltrate. Higher baseline levels of these MDSC-miRNAs in plasma identified melanoma patients resistant to immune checkpoint inhibitors (ICI) but did not discriminate response to BRAF/MEK inhibitors. Their results imply that plasma MDSC miRNA might impair ICI-induced response and may represent the first predictive blood biomarker of resistance to ICI.

Congratulations to Dr. Marisol Soengas on receiving the Fritz Anders Lecture Award!

Congratulations to Dr. Genevieve Boland (Massachusetts General Hospital), Dr. David Liu (Dana Farber Cancer Institute),and Dr. Srinivas Saladi (Massachusetts Eye and Ear Infirmary), as well as their mentors Dr. Keith Flaherty (Massachusetts General Hospital), Dr. Eliezer Van Allen (Dana Farber Cancer Institute), and Dr. David Fisher (Massachusetts General Hospital) for receiving the MRF Breakthrough Consortium – BMS Young Investigator Research Team Award to Advance the Field of Translational Immuno-Oncology for their project entitled “Characterizing the Role of the Hippo Pathway During Melanoma Immunotherapy”.

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Announcements

MRA Announces $8.2 Million for New Grant Awards to Advance Melanoma Research

The Melanoma Research Alliance (MRA), the largest non-profit funder of melanoma research, announced funding for 33 innovative research awards totaling $8.26 million on April 30, 2019. The newly selected research awards will address critical unmet needs in melanoma detection, prognostication and treatment. Five awards – three of which were generously funded by the Michael and Jacqueline Ferro Family Foundation – will investigate ways to better harness artificial intelligence to improve the early detection and prognosis of melanoma. Several other projects will examine novel drug targets, new treatment approaches for brain metastases, and ways to overcome targeted therapy resistance. Learn more here.

Congratulations to the following SMR members on receiving an MRA award!

Congratulations to Dr. Rhoda Alani (Boston University) on receiving an MRA Established Investigator Award for her proposal entitled “Epigenetic Regulation of Resistance to Targeted Therapies in Melanoma”.

Congratulations to Dr. Adam Hurlstone (University of Manchester) on receiving an MRA Established Investigator Award for his proposal entitled “DGAT1 is a novel melanoma oncogene”.

Congratulations to Dr. Jean-Christophe Marine on receiving an MRA Established Investigator Award for his proposal entitled “Eradicating melanoma drug-tolerant cells”.

Congratulations to Dr. Neal Rosen (Memorial Sloan-Kettering Cancer Center) on receiving an MRA Established Investigator Award for his proposal entitled “Preclinical development of a disrupter of BRAF-containing dimers”.

Congratulations to Dr. Yardena Samuels (Weizmann Institute) on receiving an MRA Established Investigator Award for her study entitled “Studying the effects of intra-tumor heterogeneity on anti-tumor immunity”.

Congratulations to Dr. Daniela De Zio (Kraeftens Bekaempelse) on receiving an MRA Young Investigator Award for her proposal entitled “The multifaceted Ambra1-based signaling in melanoma response to therapy”.

Congratulations to Dr. Michal Lotem (Hadassah Hebrew University Medical Center) on receiving an MRA Pilot Award for her proposal entitled “Spliced immune receptors for immune regulation and melanoma immunotherapy”.

Melanoma Meetings Around the World

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