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

Volume 35 | December 2020

Jarem Edwards and Karla Lee (editors)

Letter from the SMR President

SMR President, Ashi Weeraratna, PhD

Dear SMR Community,

I begin my first year as President with a fervent wish that all of you are keeping healthy. For those in Asia, and Australia, and to some extent Europe, you are the lucky ones, with the virus under control in some parts of your continents, and manageable in others, and I have even seen some posting pictures of in-person conferences! I’m jealous! In the Americas, that remains a dream still, but thanks to the efforts of our immunology and infectious disease colleagues, there’s a light (or three!) at the end of the tunnel.

I want to start out by thanking the outgoing committees and welcoming our new members to the Executive and Steering Committees. I want to thank Georgina Long, who led the Society for the last two years, and who handled with aplomb the different challenges of this last year with its difficult and demanding decisions. Keith Flaherty, as outgoing, past president, finally gets a break, and will be rotating off the Executive committee, currently composed of Anja Bosserhoff, our treasurer, Liz Patton, our Secretary Elect and Mike Davies, our President-Elect. Congratulations to all of them, as well as the new members of our Steering Committee, Vito Rebecca, Carmit Levy and Alex Menzies. We continue to be supported by the amazing team at Site Solutions, spearheaded by Sarah Hughes and Debra Marshall, for whose guidance we are always grateful. Welcome to all- I look forward to working together on new initiatives!

While the world has changed dramatically in the last year, impacting our clinics and our science, I am pleased to report that many of our members continue to produce great science, and our supporting foundations have remained in solid standing- we are more fortunate than other fields in this respect. Members of SMR continue to publish the highest level science, breaking ground in everything from the very basic molecular and cellular mechanisms of melanoma to new clinical insights. This year, three of our very own, Drs. Levi Garraway, Toni Ribas and David Fisher were also elected to the National Academy of Medicine.

Looking forward, my goal is to create a Society that continues to be inclusive, and to make sure that all of our membership feels a valued part of our Society. It is wonderful to see growing representation in Latin America, to add to our considerable Australian, European and North American influences. We look towards building both this and representation from Asia and Africa as well. Initiatives on gender diversity have had a significant impact on our Society over the past several years. My hope is to bring to bear these experiences on much needed efforts in racial equity as well. While it is early in my tenure, I have a lot of ideas in this area and am excited to put some of them in action. Importantly, I would like to know from all of you, the members of this Society, what are some initiatives and areas you would like to see developed. It can really encompass anything, whether in terms of science directions, or equity initiatives. How can our Society better serve you, both at and beyond our annual meeting? And speaking of the annual meeting, I know many of you are curious as to what the next meeting may hold, and we are still discussing. We will soon make a decision and alert our membership to it, so stay tuned for that email!

I will close by thanking all of you for your hard work, and solidarity during these challenging times. Please be kind to yourself- in these pandemic times it is easy to fall into the trap where you feel like all of those around you are flourishing, and you are barely getting by- believe me, we all feel that way from time to time. I often describe it as treading water just to keep my nose in the air- and that’s despite all of the great privilege I have, like superb administrative help, incredible trainees, and a supportive family. So, please, take each day as it comes, do the best you can, and take care of both your physical and mental health. I look forward to serving all of you as President and wish you all the best for a quiet and restful holiday season.

Sincerely,

Ashi Weeraratna, PhD, SMR President

2020 Virtual SMR Congress Highlights

This year saw the first ever virtual SMR congress which was held on 28th October and chaired by Dr. Mike Davis and Dr. Keith Flaherty. We heard a number of excellent recorded presentations from invited faculty with live Q&A sessions after each presentation. In this section we briefly summarise these presentations.

By Gretchen M. Alicea Ph.D. and Vito W. Rebecca Ph.D.

Dr. Aviv Regev presented a tour de force effort leveraging single cell genomics and novel computational analyses to understand tumorigenesis, metastases and resistance. Her work investigated why some patients derive no clinical benefit to anti-PD-1, finding a role for Myc and CDK targets. Dr. Regev dissected the immune exclusion programs using a cancer cell-tumor infiltrating lymphocyte (TIL) co-culture model coupled with pooled CRISPR screens and scRNAseq. In her final slides, she presented an innovative “build-a-melanoma” project that delineated how key melanoma mutations combine to cause hallmark phenotypes (i.e., melanoma aggressiveness, tumor microenvironment remodeling).

Dr. David Fisher presented interesting and unpublished work focused on a well-established positive linkage of melanoma incidence and Parkinson’s disease. Dopamine treatment has been identified to increase melanoma incidence; however, the molecular mechanism is unclear. His work demonstrated how L-DOPA levels may influence skin pigmentation (pheomelanin or eumelanin expression) and ultimately impact melanoma incidence. As a possible solution to prevent melanoma induced by dopamine treatment in red hair patients, he proposes to modulate skin pigmentation by antagonizing the MITF pathway using a SIK inhibitor (previously shown to darken the skin of mice).

Dr. Jean-Christophe Marine presented exciting data from his group focused on understanding the phenotypic plasticity and developmental cellular hierarchy that enables melanoma cells that comprise minimal residual disease to metastasize and resist therapy. He touched upon the magnitude of melanoma state diversity, the extent of cellular plasticity, and efforts to define the functional contributions of each cellular state to metastasis and resistance. Notably, he identified NRAS-mutant melanoma cells that adopt a neural crest stem cell lineage program. Dr. Marine also presented data that phenotype switching in vivo may be a requirement for metastasis to occur.

By Jarem Edwards (Ph.D candidate)

Dr. Yardena Samuels, recipient of the SMR Estela Medrano Award, and Dr. Stefani Spranger, recipient of the SMR Young Investigator Award, each gave provoking talks at this year’s SMR virtual meeting.

Dr. Samuels challenged the way we think about mutational load as a predictor of anti-tumor immunity and response to immunotherapy. Firstly, in elegant mouse models her team showed that intratumoral heterogeneity (defined by both clonal genetic diversity and the number of clones) were additional factors that needed to be considered in the context of the mutational landscape. Minimizing tumor heterogeneity exposed reactive neo-antigens to better immune detection, which limited tumor aggressiveness. Secondly, in a separate study, HLA-peptidomics revealed that bacterial antigens bound to HLA class 1 and 2 peptides exist in melanoma tumors and could in themselves be immunoreactive, suggesting that this class of antigens could potentially contribute towards the overall anti-tumoral response. Lastly, altered peptides, which are produced in tryptophan-deprived environments by ribosomal stalling, likely also represent the repertoire of HLA-presented peptides in melanoma.

Dr. Spranger emphasised the importance of CXCL10/CXCL9-expressing CD103+ cross-presenting dendritic cells as an important population responsible for the recruitment of T cells into tumors. Beta-catenin expression in tumors was inversely correlated with this dendritic cell population, thereby limiting T cell infiltration. Targeting the beta catenin pathway in tumors might help to boost effector anti-tumor T cells and improve the efficacy of current immunotherapies. In the second part of her talk, Dr. Spranger showed that lung cancer cells injected at different sites (skin (subcutaneous) vs. lung (intravenous)) produced transcriptionally distinct T cell infiltrates. Subcutaneously derived T cell infiltrates, though lower in numbers at baseline, expanded in response to anti-PD-1+ anti-CTLA-4 immunotherapy and displayed a conventional effector/exhaustive phenotype. In contrast, T cells from the lung did not respond to immunotherapy and displayed a memory phenotype.

By Claire Hardie M.D., Ph.D.

Dr. Maria Soledad Sosa, assistant professor for the Department of Pharmacological Sciences, Mount Sinai Hospital, gave a wonderful talk entitled ‘Midkine reactivates dormant disseminated tumor cells’. Her work has demonstrated that NR2F1 is upregulated in disseminated tumor cells (DTCs) during dormancy phase, and that patients with high NR2F1 DTCs across different cancers have reduced disease recurrence. The team has identified that midkine (MDK) high melanoma is found in overt metastases and that MDK may block the dormancy of DTCs. Current exciting work on these topics is awaiting publication. Their lab is concurrently undertaking a clinical trial for dormancy inducing therapy using atRA and 5-Aza-C which has promising early results.

Another superb talk was given by Professor Jennifer Wargo on ‘The role of the gut and tumor microbiome in melanoma’. Her team at the MD Anderson Cancer Center are continuing to make major advances in understanding the role of the gut and tumor microbiome in response to cancer therapies, in particular immunotherapies. Groups working hard to identify optimum consortia of microbes to improve patients’ response to therapy and numerous studies are underway incorporating modulation of the gut microbiome in combination with response to immune checkpoint blockade.

By Rebecca Lee M.D., PhD.

Prof. Rizos gave an excellent overview of circulating tumour (ctDNA) in melanoma. She described some of the challenges including the difficulty in detecting ctDNA when tumours are small and if metastases are present in certain organs such as the brain. She presented the potential applications for ctDNA, for example, work her lab has performed in stage III melanoma has shown that ctDNA is an independent prognostic biomarker. In addition, it can be a predictive biomarker of response to immunotherapy and can be used to identify mechanisms of resistance to targeted therapy. There is huge potential for ctDNA to be used in melanoma, however it will be important to develop the right assay for the context in which it is used.

By Karla Lee M.D (Ph.D candidate)

Dr. Anja Bosserhof opened her excellent talk by discussing the importance of mast cells in the melanoma tumour microenvironment. She went on to talk about how the tumour microenvironment has an impact of many differing levels: cellular, stiffness, pH, composition. Dr. Bosserhof explained how to fully understand the potential and the mechanisms at work we need a combination of in vitro attempts, 3D biofabrication, in vivo models and human data/samples.

Dr. Christian Blank opened the clinical sessions with a very interesting presentation on neoadjuvant treatment for melanoma. He presented data from the OpACIN study, discussing important issues around dosing and toxicity amelioration. He then moved on to the OpACIN-neo study: as we expected, at 24 month recurrence free survival remains significantly higher for patients with pathologic response compared to non-responders. An extension cohort has emerged from this work; the PRADO study involved placement of index node markers before neoadjuvant combination immune checkpoint inhibition, removal after this systemic treatment and pathological examination to determine the next stage of treatment to be provided, as per the trial design. Dr. Blank explained the importance of IFN gamma, and how this can be combined with tumor mutational burden for prognostication. He described the use of IFN gamma in the DONIMI trial. Finally he summarised some other exciting work going on in the neoadjuvant space internationally, and expressed hope that the next 2 years would provide a greater definition of the key signatures of response.

Prof. Grant McArthur gave a fascinating presentation on overcoming resistance to targeted therapy. He described how the combination of anti-PD-1 or anti-PD-L1 to BRAF and MEK inhibition improves progression free survival and duration of response to targeted therapy. He explained that while further follow up is required to assess the impact on overall survival, the progression free survival curves have not yet shown signs of plateauing. Prof McArthur emphasised that while the toxicity attributed to these triple therapy regimens remains undoubtedly higher, they can and have been delivered safely to patients. He concluded by showing the subsets of patients with an inflamed tumor microenvironment or higher tumor mutation burden may obtain greater benefit, but further research is certainly needed in this area.

Prof. Georgina Long delivered a thorough review of the current state of play in immunotherapy. She presented a slide of overall survival in metastatic melanoma, highlighting progress made to date with 50% overall survival at 5 years for combination immunotherapy. She showed results from the 3-triple therapy (BRAFi + MEKi + anti-PD-1) studies which have regrettably failed to meet their primary endpoints, but provided valuable data. Prof Long moved then to summarise the 3 large adjuvant studies, where ~50% reduction in risk of recurrence has been seen compared with placebo after 12 months of treatment. She touched on a number of other adjuvant studies including the phase 2 IMMUNED study and Checkmate 915. The issue of resistance is clearly key in this context and Professor Long discussed resistance risk calculations being used currently in the clinical setting. She then took us on a whistle stop tour of key pre-clinical papers published in the past 5-10 years across a number of research areas. Finally, she addressed the question of “where to next?” with neoadjuvant therapy, personalization and stratification of therapy and potentially the gut microbiome being key areas to watch.

SMR 2021 Congress

The 18th International Congress of the Society for Melanoma Research will be held in New Orleans on October 28th - 31st, 2021.

The SMR holds annual meetings to provide researchers an opportunity to collaborate, meet, and share ideas about all forms of melanoma research. Past conferences have produced overwhelming positive feedback and this coming conference will be no exception.

Please save the date and prepare to submit an abstract! Abstract submission deadline will be announced at a later date.

Other relevant meetings around the world 2021

SMR MEMBER NEWS

Please remember to share important milestones with your colleagues.

Congratulations to Dr. Yardena Samuels, recipient of the SMR Estela Medrano Award, and to Dr. Stefani Stranger, recipient of the SMR young Investigator Award.

Congratulations to SMR community members featured on the Highly Cited Researchers 2020 List.

Congratulations to Dr. Richard Scolyer on receiving the RCPA recognition and receiving the University of Sydney's annual Alumni Award.Dr. Scolyer will receive the highest award bestowed by The Royal College of Pathologists of Australasia RCPA, the RCPA Distinguished Fellow Award. This great honour was made in recognition of his position as one of Australia’s most distinguished medical researchers. Professor Scolyer was recognised by his peers for his outstanding scientific contributions, academic leadership, clinical excellence and mentoring of young colleagues.

Congratulations to Dr. Georgina Long, who has been recognized in the 2020 Queen’s Birthday Honours List announced today by the Governor-General. Professor Long has been appointed as an Officer (AO) of the Order of Australia (General Division) for distinguished service to medicine, particularly, to melanoma clinical and translational research, and to professional medical society.

Melanoma Research Foundation 2020 Award Recipients

For more than 20 years, the Melanoma Research Foundation (MRF) has advanced the field of melanoma science by supporting researchers advancing a broad scientific agenda covering prevention, diagnosis, staging and treatment. Please join us in congratulating the recent 2020 MRF Research Award Recipients, as noted below:

Established Investigator Awards

  • Linda Malkas, PhD from the Beckman Research Institute of the City of Hope for her proposal entitled “Novel Target for Melanoma Therapeutic Development”
  • Thorsten Mempel, MD, PhD from Massachusetts General Hospital for his proposal entitled “Converting Regulatory into Proinflammatory Anti-Tumor Effector T Cells”
  • Jeffrey Ravetch, MD, PhD from The Rockefeller University for his proposal entitled “Defining the Mechanisms of Resistance to Anti-CTLA4 Antibodies in the TME”

Career Development Awards

  • Lawrence Kwong, PhD from the University of Texas MD Anderson Cancer Center for his proposal entitled “CXCL9 as an Immune Anti-Melanoma Therapy in Combination with BRAF Inhibition” (Mentor: Patrick Hwu, MD)
  • Zachary Schug, PhD from the Wistar Institute for his proposal entitled “Elucidating Metabolic Changes that Occur in Melanoma Brain Metastases” (Mentor: Meenhard Herlyn, DVM, DSc)
  • Shruthy Suresh, PhD from Memorial Sloan Kettering Cancer Center for her proposal entitled “Identification of Metastatic Modulators through Zebrafish Modeling” (Mentor: Richard White, MD, PhD)

Donor-Directed Grant Funded by the Brodman Family Charitable Fund & Friends

  • Keiran Smalley, PhD from the Moffitt Cancer Center for his project entitled “Investigating the Role of a Novel Dendritic Cell Population as a Central Regulatory of a Favorable Immune Environment in Melanoma”

Volunteers for Survey

The Wayne State School of Medicine Department of Dermatology is seeking your help as a volunteer to fill out a survey about preoperative anxiety in dermatology procedures. The link to the survey can be found below. https://www.surveymonkey.com/r/JTFGRFT

Job Opportunities

Huntsman Cancer Institute

Postdoctoral Fellow Position

The University of Utah in Salt Lake City has an opening for a highly motivated post- doctoral fellow to join the laboratory of Dr. Sheri Holmen at the Huntsman Cancer Institute. The Holmen lab is interested in studying the mechanisms of melanoma brain metastasis with an emphasis on identifying targets for clinical translation. Current projects focus on the AKT pathway and downstream effectors that mediate this process. (Related publications: Cho et al. Cell Reports 2015; Kircher et al, Molecular Cancer Research 2019). For more information about the Holmen lab visit our website at https://uofuhealth.utah.edu/huntsman/labs/holmen/

Requirements: Candidates should have recently received a Ph.D. (or equivalent) degree or be close to obtaining their doctoral degree with experience in cancer biology. Experience in melanoma, molecular and cellular biology and mouse genetics is preferred.

To apply: Interested applicants should submit a cover letter, curriculum vitae, and a list of three references to Dr. Sheri Holmen via e-mail at sheri.holmen@hci.utah.edu.

Post Doctoral Position

The Judson-Torres Lab at the Huntsman Cancer Institute is looking for a highly motivated PhD level researcher to study cellular heterogeneity in normal and cancerous mouse and human skin. Additional project details are available on our lab website (www.judsontorreslab.org).

Job Summary: The Judson-Torres Lab is a part of the Huntsman Cancer Institute and Departments of Dermatology and Oncological Sciences at the University of Utah, School of Medicine. The open position provides an opportunity for postdoctoral training in a vibrant and highly collaborative setting. The work seeks to advance our understanding of the tumorigenic potential of individual cells during melanoma initiation and progression. This will entail the design and execution of experiments as well as the presentation of key findings in internal and external forums such as campus seminars, international meetings and in published form. There will be opportunities to develop leadership and independence along lab related research themes. The position will commence on or before January 1st, 2021.

The Judson-Torres Lab looks to principles of diversity, inclusion, equity, anti-racism and anti-oppression to inform our development, training, collaborations and offerings. Through these efforts, we aim to both improve and promote within our own group and the broader community, awareness of and appreciation for differences including, but not limited to, race, sex, gender identity, ethnicity, national origin, culture, sexual orientation, religion, age, and ability. Please apply here: http://utah.peopleadmin.com/postings/107828

New Mobile App for the SMR Community

The NEW SMR Communities Mobile App is now available to download!

This new app exclusive to SMR members offers the ability to network with other members, browse employment opportunities and stay up to date on melanoma related news right from your phone. Download our official app by visiting the Apple Store or Google Play and search "SMR Community"

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