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

Volume 30 | January 2019

Edited By: Marie Webster, Ph.D. & Ken Dutton-Regester, Ph.D.

Letter from the SMR President

SMR President | Georgina V Long

A War-Zone in need of a Lifeline

I am so honoured and excited to receive the baton as SMR president from Keith Flaherty, and work with Keith (as past-president), Ashani Weeraratna (as president-elect) and the executive committee to lead the organisation (Anja Bosserhoff as treasurer and Michael Davies as secretary). The members of this prestigious society have been responsible for some of the ‘world first’ discoveries in cancer, as well as cell and molecular biology in general, and I am very proud to be president.

For the last 10 years we have witnessed the revolution of effective drug therapies in melanoma clinics all around the world. As a clinician, I see ~70 patients a week with stage III or IV melanoma, and I see and talk to every single one of them. Some patients come every 4 weeks, others every 6 weeks and others every 3-6 months. I know them well. Some are survivors, pulled from the brink of death, and are often left feeling anxious about when the dreaded melanoma will return or grow. Most of them will be fine long-term. Others live through the elation of surviving, only to find the melanoma eventually catches up, and others still are not so lucky from the get-go.

This latter group of patients are my focus. It is desperate, it is a war-zone, and it is awful. They are often young, full of hope, in denial for the sake of their young families (or their parents if they are very young), and they progress through every treatment or trial we try. I can name these patients: David Day, Melinda Beaumont, George Sponiar, and the list goes on and on.

At this time, we have no life line for these patients who are facing death.

Who are they? How do we identify them? How do we select them out to learn more about the biology of their particularly treacherous melanoma, and how can we stop their death? We are in a war-zone, and these patients make up approximately 20-30% of all those with advanced melanoma. We call them ‘super-progressors’ in my institution, Melanoma Institute Australia.

Why is this important to SMR? Because the scientists who are members of SMR have lived through this journey and were responsible for the revolution, whether their focus is on pigment cell and melanocyte biology, prevention, risk, metabolism, T cells, B cells, NK cells, cell biology, germline/somatic genomics, epigenetics etc. It has all contributed to understanding this deadly disease and much more. And most importantly, the SMR community has the tools to fix this new problem.

One strategic move in this war is to start at the worst of the worst progressors – the patients we can name. The patients where nothing works, the ones we cannot save, not even for a few months. Their biology will teach us. Because anti-PD-1 + anti-CTLA-4 is our most effective therapy, we can view these drugs as a tool to identify the worst biology. It is not that we want to examine anti-PD-1+ anti-CTLA4 resistance per se, but more that we want to identify bad biology so as to focus our sharpened research tools to eradicate cancer quickly.

If, like me, drug therapy is where you are in your research - drown out the noise of drug companies and the latest phase 1 trial, and focus on the issue with your tools and expertise. Whatever that be; metabolism, epigenetics, cell signalling pathways, proteomics, genomics etc. Apply your tools to this pressing problem – patients who die without any response to drug therapy…ever. Understanding these patients will give us answers; the next drug, the next trial, the biology. And most importantly, what we learn in melanoma first will impact all cancer. We are at the forefront, and we plan to keep it that way.

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Melanoma News

The SMR congress in Manchester was a great success! We were welcomed to the meeting by Dr. Richard Marais and Dr. Keith Flaherty followed by the keynote address, which was given by Dr. Jennifer Wargo. Dr. Wargo emphasized the importance of team science and highlighted research which would be presented during the congress. She proposed that a powerful way to better understand response is via reverse translational research where findings go from bedside to bench and back again.

Women and Science Session at the SMR

Led By: Liz Patton and Ashani Weeraratna

This year’s Women and Science session was nothing short of amazing, only fitting for a meeting set in Manchester, the home of Emmeline Pankhurst, and the birthplace of the suffragette movement. We had planned for our usual 75-80 people, but it felt like the whole meeting showed up! When Liz and I got up on stage and looked out at the sea of people, men, women, junior, senior, I had to choke back tears of joy. Thank you to all of you who came, it means the world that we work in a community that is so incredibly supportive.

So, on to the meeting! What we wanted to do this year was present some problems, potential solutions, and concrete actions we can take as leaders and mentees. The topics discussed were:

  • Work/Life balance- Liz Patton and Janice Mehnert
  • Bias in Publishing/ Grant panels- Vijay Setaluri and Kristen Mueller
  • Mentorship- Keith Flaherty and Jen Wargo
  • Leadership- Richard Marais and Marisol Soengas
  • Counteracting Sexist Behavior at Work- Ashi Weeraratna and Ze’ev Ronai

We are planning to put together a white paper on this, so we will simply list key bullet points and takeaways from the discussion. We’d like to strongly encourage our leaders in the community to think about the suggested actions, and how you’d go about implementing these in your workplaces, if they are not already in place. We hope that next year’s women in science session will be equally successful, and please don’t hesitate to reach out with your thoughts!

Work/Life Balance- Liz Patton and Janice Mehnert

  • Foster support at transition from postdoc to faculty or residency/fellowship to faculty as this is where many are lost due to inadequate family or career support.
  • Look for opportunities to support those with families to continue to stay part of the field (child care at conferences/funding for travel for those who may be on short leave).
  • Encourage that leave policies already in place at many institutions actually are able to be fully utilized by faculty (many do not take for perception that they are not “serious”).
  • Strengthen networks for those who do not have alternate role models to turn to for advice (mid-career faculty commented they would have found this useful in the early years of their faculty appointments).
  • Voice the reality that during the early years of pregnancy/child rearing productivity may naturally slow down a bit…and often will pick up again later.

Bias in Publishing/ Grant panels- Vijay Setaluri and Kristen Mueller

  • Reviewers generally review in good faith, but unconscious bias exists and can affect the success of women and underrepresented groups.
  • Blinding applications or manuscripts is one way to address potential unconscious bias in peer review, however, there are issues with this, including reviewers guessing who the applicant/author is and journal editors and program staff are not usually blinded. Nature Journals ran an experiment giving authors the option of blinded review (only reviewers were blinded, not editors), and they found that the acceptance rate of blinded papers was lower than those that did not opt to have blinded review.
  • Increasing the representation of women on grant review committees or as reviewers on papers is a good idea, but they also have similar implicit biases as men. Increasing the representation of women reviewers has important downstream effects, such as bringing their networks into the fold.
  • There are ways to mitigate implicit bias in the review process. These include implicit bias training and adjusting language in RFPs and review criteria to be more gender neutral. Melanoma Research Alliance took the latter approach in 2017 when they discovered that the % of female applicants was higher than the % of female awardees. This resulted in the gender parity in their most recent review cycle, where the % of female applicants matched the % female awardees.

Mentorship- Keith Flaherty and Jen Wargo

  • Diversifying mentor team so that coaching can be found for navigating academic career building and life.
  • Using mentor team to frequently discuss project portfolio to make sure it is aligned with work/life balance.
  • Establishing open communications with all mentors and relevant head of division/department/etc regarding life plans and personal targets for productivity.

Leadership- Richard Marais and Marisol Soengas

  • Leadership should ensure gender-balanced committees and coordinate career-development activities, particularly, seminars or workshops.
  • Active mentorship from senior faculty (males and females) to encourage female researchers to apply for grants and awards. Confidence is often an issue.
  • Targeted searches for female candidates by institutes with job openings if applications by female candidates are low.
  • Institutional policies to favor maternity & paternity leaves (technician support, travel grants…).

Counteracting Sexist Behavior at Work- Ashi Weeraratna and Ze’ev Ronai

  • Do your homework- for trainees- ask around about the lab environments you are considering. It’s not just the mentor, but also the staff you need to consider. For faculty- talk to other female faculty- and ask questions about gender equity.
  • Seek allies: Find mentors beyond your immediate environment- people you respect in your field, who can help mediate on your behalf. Seek these mentors in and outside of your institute.
  • Call out microaggressions- microaggressions are the little almost unconscious acts that undermine your confidence in the workplace-64% of women experience these, and women of color experience these disproportionately more. Microaggressions include having your qualifications or judgement more closely examined than a male colleagues, having someone explain to you things you already know, or having colleagues take an idea seriously that you have previously voiced only when a male colleague repeats it. While seemingly trivial when taken individually, microaggressions mount over time, so calling them out when you see them is important.
  • Amplify women- Give credit to the woman or minority whose ideas you are voicing, invite women and minorities to leadership positions, nominate them for awards, make sure there is gender equity in speaker panels, and don't just be a mentor, be a sponsor.
  • Institutionalize equality- make it easier for women to have children, make anti-sexism policies a part of the culture, so no-one has to tolerate sexism and harassment in fear.

In conclusion, we are making great strides in the scientific community. We are moving from awareness of the issues to concrete actions. SMR itself has wonderful advocates for women and minorities- check out Rohit Thakur’s series on Women in Melanoma Research featured on the website! To all the men who are allies and amplifiers and the women who are taking the punches so that the way forward is easier for those behind, we thank you. Below, find some interesting Twitter hashtags along those veins. We are proud of our society, that started addressing these issues years ago, and is making progress on so many fronts.

Best to you all,

Ashi and Liz

STEM for Women: Empowering Women in Melanoma Research

By: Rohit Thakur

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 was 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 first interview, which is currently on the SMR website (https://www.societymelanomaresearch.org/), features Dr. Ashani Weeraratna (Wistar Institute) and Dr. Marisol Soengas (CNIO Spain). In this series, Ashani talks about following her passion to pursue science, and Marisol shares her guidance for early career trainees on how to find the right lab environment and how to ask important scientific questions. Even though they are separated by thousands of miles, Ashani and Marisol’s friendship and dedication to discovering cures for melanoma drives their research forward. They set an example for generations to come on how to forge and maintain international collaborations and life-long friendships that result in cutting-edge science. Ashani and Marisol, emphasize the importance of being aware of the cultural differences when making career transitions and urge early stage researchers to be more confident. Ashani, the president-elect of SMR, bears this responsibility with great pride and hopes to bring together melanoma researchers worldwide and to keep the SMR tradition of team science alive.

Different routes towards the same end goals – a strategy of cancer cells or cancer research?

By: Amanpreet Kaur

The annual congress of SMR covered topics ranging from immunotherapies, metabolism, microbiome, tumor microenvironment and most importantly resistance mechanisms. Here, I cover some studies examining the role of the microenvironment on melanoma progression and therapy resistance, but only scratch the surface of what the field is investigating at large.

Yardena Samuels, from Weizmann Institute of Science, is interested in identifying novel melanoma antigens shared among patients that generate tumor infiltrating lymphocyte response in order to develop these antigens as novel therapeutic targets. She found that higher mutational load combined with increased intratumoral heterogeneity is associated with a better response to checkpoint blockade. Andrew Aplin’s lab at Thomas Jefferson University is developing treatment strategies for patients with BRAF mutant tumors that are intrinsically resistant to BRAF and MEK inhibitor or are wild type for MAPK pathway mutations and progress on immunotherapies. His group has demonstrated the role of neuregulin 1 (NRG1) in protecting melanomas from MEK inhibitors. NRG1 binds to ERBB3 and activates PI3K/AKT pathway but can be easily targeted by using antibodies against ERBB3 or by BET inhibitors. However, NRG1 in tumors is likely derived from cancer associated fibroblasts (CAF) and there’s little production of NRG1 by tumor cells themselves, thus cementing the key role of tumor microenvironment in regulating melanoma progression. His group is also developing an in vivo reporter system based on cell cycle mediated uncoupling of E2F, which can be measured using firefly luciferase, to study activation of CDK4/6 pathway.

Several labs are studying the effects of cellular mechanics and the extracellular microenvironment (ECM) on cell migration. Eric Sahai, from The Francis Crick Institute, used intra-vital two photon imaging to show that only a subset of melanoma cells in a tumor are migratory, however, there is a diversity of cell shapes among the migratory cells. Similarly, Victoria Sanz-Moreno at the Barts Cancer Institute, showed in an orthodontic model that the cells in the tumor body are spindle shaped while at the periphery, the cells are more of an ameboid shape. These ameboid cells permeabilize the microenvironment at distant sites to promote colonization. Inhibition of ROCK, Myosin II, or STAT3 may be a way to target these dangerous cells. Ashani Weeraratna, from the Wistar Institute, discussed how changes in the extracellular microenvironment during aging may affect the metastatic distribution of tumor cells in young and aged patients. A highly crosslinked ECM in a young microenvironment is restrictive for migrating melanoma cells due to their large nuclear size. Breakdown of these crosslinks during aging allow the large nucleus of tumor cells to squeeze through the tumor ECM, thereby promoting cellular migration.

Drug resistance and metastasis are two major issues faced by melanoma patients and clinicians worldwide. The SMR congress program showcased the collaborative efforts of various groups in combining their expertise to gain more insights into tumor biology. This year there was an increasing emphasis on the use of combinatorial approaches exploiting tumor immunology, metabolism, cellular signaling and the microenvironment, leading to new hope that it might be possible to create eagerly awaited cures for melanoma.

Cancer Immunotherapy Awarded the Nobel Prize

By: Ken Dutton-Regester

In October last year, the 2018 Nobel Prize in Physiology or Medicine was awarded to the discovery of cancer therapy by inhibition of negative immune regulation. The Nobel was jointly awarded to James P. Allison (MD Anderson Cancer Center) and to Tasuku Honjo (Kyoto University) for the discovery and mechanism of CTLA4, and PD1 and PD-L1 checkpoint in immune regulation, respectively. Regarded as the fourth pillar in cancer therapy (behind chemotherapy, radiation and targeted drug strategies), the prize recognizes the completely new approach to treating cancer by harnessing the immune system. As SMR members, we would all be aware of the critical role the melanoma field had in demonstrating the effectiveness of immunotherapy and laying the foundations for use in other cancer subtypes. In addition to congratulating Dr. Allison and Dr. Honjo, the SMR would like to recognize all the researchers, clinicians, advocates and patients on clinical trials that ultimately led to the success of immunotherapy in treating cancer. This is a significant milestone that demonstrates to the wider public that their investment in medical research is meaningful and having a definitive impact in the world.

SMR Member News

Congratulations to Mayo Clinic physicians Matthew S. Block, MD, PhD and Tina J. Hieken, MD, who in collaboration with University of Minnesota physician Shernan G. Holtan, MD, have received a Stand Up To Cancer (SU2C) Catalyst award to fund a melanoma neoadjuvant clinical trial and associated correlative research! The trial, NeoACTIVATE, is a pilot study testing two novel approaches to the treatment of patients with high-risk stage III melanoma, as guided by BRAF mutation status. Patients with BRAF-mutant melanoma will receive neoadjuvant vemurafenib, cobimetinib, and atezolizumab, whereas patients with BRAF wild-type melanoma will receive neoadjuvant cobimetinib and atezolizumab. Following neoadjuvant therapy, all patients will undergo surgery followed by adjuvant atezolizumab. The primary endpoint of the study is recurrence-free survival in each cohort; secondary endpoints include pathologic complete response rate in each cohort, as well as several immune, microbiome, and tumor microenvironment-based correlative assays. For more information on the NeoACTIVATE trial, please refer to the ClinicalTrials.gov web site: https://www.clinicaltrials.gov/ct2/show/NCT03554083?term=NeoACTIVATE&rank=1

Congratulations to Yana Najjar, M.D. and Greg Delgoffe for receiving a DoD Translational Team Science Award! Their grant will explore Metabolic Remodeling of the Tumor Microenvironment to Improve the Efficacy of Immunotherapy!

SMR Members elected as AAAS Fellows

In further recognition of success of our members, the SMR would like to congratulate Dr. Jeffrey Gershenwald and Dr. Patrick Hwu of the MD Anderson Cancer Center for their election as Fellows to the American Association for the Advancement of Science (AAAS). Election as a Fellow, a tradition that began in 1874, is an honor bestowed upon AAAS members by their peers. From a field of 416 newly appointed Fellows covering 24 scientific disciplines, Jeffrey and Patrick were recognized for the following contributions:

  • Jeffrey Gershenwald, M.D., professor of Surgical Oncology, for distinguished contributions to the field of clinical and translational medicine, particularly for evidence-based advances in melanoma staging and prognosis and molecular classification of melanoma.
  • Patrick Hwu, M.D., head of the division of Cancer Medicine, chair of the Melanoma Medical Oncology, for distinguished contributions in the development of novel cancer immunotherapies, vaccines, and rational combinations of targeted immunotherapies, and for improving treatment outcomes for cancer patients.

Congratulations!

Congratulations to SMR Award Recipients!

Jeffrey E. Gershenwald, M.D. - Leadership Award
Vito Rebecca, Ph.D. - Christopher J. Marshall Award
Caroline Robert - Lifetime Achievement Award
A. Hunter Shain, Ph. D. - Young Investigator Award
Jennifer Wargo, M.D., M.M.Sc. - Outstanding Research Award

not pictured: Neal Rosen, M.D., Ph.D. - Lifetime Achievement Award

& Congratulations to all of the Travel Award Recipients!

Listed Alphabetically: Rached Alkallas, Daniela Cerezo Wallis, Stephen Douglass, Mona Foth, Thibault Houles, Bradley Krasnick, Sonia Leonardelli, Aija Ozola, Shivshankari Rajkumar, Sangeetha Reddy, Manoela Tiago, and Gregory Watson

Announcements

MRF Award announcements for 2019

The MRF will accept applications from January 2- March 1, 2019 for the 2019 award cycle. The deadline is March 1, 2019 at 5 pm EST. All submissions, notifications and critiques will be completed entirely online through ProposalCENTRAL (https://proposalcentral.altum.com/).

CURE Ocular Melanoma Team Award (CURE OM Team) The CURE OM Team Award provides funding of up to $125,000 per year for two years for research focusing on ocular melanoma. Teams should consist of a PI and at least one co-PI, ideally from different institutions. Teams consisting of both basic scientists and clinicians are encouraged, as is the inclusion of a junior scientist.

Established Investigator Awards (EIA) The EIAs provide funding of up to $100,000 per year for two years to established melanoma researchers, or senior researchers working in closely related fields who wish to move into melanoma research.

Career Development Awards (CDA) The CDAs provide funding of up to $50,000 per year for two years to junior investigators. Researchers who are beginning a research career focused on melanoma are eligible. This year, the MRF will also offer specific career development awards focused on Pediatric Melanoma (PED CDA) and Melanoma Brain Metastases (BM CDA).

Medical Student Awards The Medical Student Awards provide funding of up to $3,000 for one year to medical students at accredited U.S. medical schools or institutions. These awards provide opportunities and funding for medical students to engage in short clinical or laboratory-based research projects focused on better understanding the biology and treatment of melanoma. Eligible areas of research can include the prevention, biology or treatment of melanoma and may focus on the study of cutaneous, ocular, mucosal or pediatric melanoma.

The 2019 Medical Student Research Grant application period is now open! Download the Request for Proposals (RFP) for more information and instructions on how to apply.

A Survey based study on approach to brain metastases from primary lung cancers and/or melanoma

The purpose of this study is to document the practices and approaches of medical oncologists practicing in Canada/the US or other parts of the world, who treat PRIMARY LUNG CANCERS and/or MELANOMA with regards to brain metastases. You are being

Melanoma Meetings Around the World

  • April 24-27, 2019: European Association of Dermato-Oncology (EADO) Congress, Venue: Maison de la Chimie, Paris, France, Dates: April 24-27, 2019, Website: eadoparis2019.com
  • June 17-21, 2019: ESDR/EADV Summer School in Molecular Tools in Dermatological and Pigment Cell Research, Location: Location: Orsay, France, Website: eadv.org/eadv-school/279
  • June 21-23, 2019: MASCC/ISOO 2019 Annual Meeting on Supportive Care in Cancer, Location: Location: San Francisco, California, Website: masccmeeting.org/2019
  • September 7-11, 2019: 31st European Congress of Pathology, Location: Nice, France, Website: esp-congress.org
  • November 20-23rd, 2019: Society for Melanoma Research Congress, Location: Salt Lake City, Utah, Website: societymelanomaresearch.org/congress

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