Volume 26 | May 2017

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

Letter from the SMR President

It’s been 6 months since we assembled in Boston for the 14th SMR Congress. Our field continues to grow in no small part due to your efforts. It is increasingly challenging to stay on top of the various fronts on which advances are being made. A quick check of the number of Medline citations by year (since the SMR was formed in 2003) shows that we are on track for another all-time high and more than twice the number of papers per year than the mid-2000’s.

Digesting all of these insights is beyond what any of us can manage. At SMR we aim to keep investigators abreast of the most impactful findings in the field. We have relied on the annual congress for this purpose, but are increasing our efforts to serve this function throughout the year. This newsletter is a component of that commitment, but we have more to do. The SMR leadership are committed to playing a more continuous role in serving our membership. Active discussion are underway on this topic and how best to use our website, email, and publications to provide highlights from the field and perspectives on new findings. We will be recruiting members to help with this effort in the near future. While we have seen striking impact from immunotherapy and signal transduction targeted therapy for patients with advanced melanoma, it is becoming very clear that we are not providing the type of long-term disease control for a large proportion of patients that is achieved by some. This is where the SMR community comes in. We need to push on fronts: better understanding of melanoma susceptibility, early detection of primary tumors, better defining metastatic risk, early detection of distant spread, and so on. We need scientific and clinical partnership to more completely understand who benefits from the therapies that began to enter clinical practice 6 years ago, who does not, and why. This is melanoma precision medicine 2.0. Discoveries in this area will not only increase our confidence in offering the available therapies to those patients most likely to benefit, but will also provide us with fingerprints of melanomas that survive despite the effects of these therapies. While high impact papers from the past two years have begun to shed light on this problem, we have not yet precisely defined the problem and potential vulnerabilities. We clearly need a new wave of therapies to make the next quantum leap in melanoma therapy and that’s going to come from concerted effort from all corners of the field.

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Meet the New Investigator: Dr. Eric Lau

This section is intended to introduce scientists who have recently started their own lab, to highlight new research in the field and promote collaborations with young investigators.

Written by: Marie R. Webster

Dr. Eric Lau obtained his Doctorate of Philosophy in Molecular Pathology in 2008 at the University of California, San Diego. During his graduate studies, he focused on the control of DNA replication and cell cycle progression in untransformed versus cancerous cells in the laboratory of Dr. Wei Jiang. In particular, he focused on the regulation of the pre-replication complex protein, Cdc6. Dr. Lau continued his training as a postdoctoral fellow in the laboratory of Dr. Ze’ev Ronai at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California.

During his postdoctoral studies, Dr. Lau worked toward elucidating the tumor suppressor and oncogenic mechanisms regulating activating transcription factor 2 (ATF2). In normal cells following genotoxic stress, ATF2 localizes to the mitochondria where it increases membrane permeability and promotes apoptosis. In late stage melanoma, high levels of PKCe stimulate the nuclear localization and transcriptional activities of ATF2, which promote increased motility and resistance to chemotherapy. In further studies, he found that ATF2 can promote chemoresistance by transcriptionally repressing the therapeutic stress-induced expression of interferon-B1. He also showed that PKCe and ATF2 mediate the invasive ability of melanoma cells through repression of fucokinase (FUK). The discovery of the role of FUK and fucosylation in melanoma presented an opportunity to investigate a previously unstudied area of post-translational modification and signal transduction in melanoma.

In 2015, Dr. Lau became an Assistant Member at the H. Lee Moffitt Cancer Center and Research Institute and an Assistant Professor at the University of South Florida. The focus of his laboratory is on elucidating the role of fucosylation in protein translation, tumor immunology, as well as cytoskeletal dynamics and how these roles contribute to the development, progression, and therapeutic resistance of melanoma.

How did you decide that you want to be a research scientist?

As a child, I grew up in San Francisco alongside my late maternal grandmother, who remains to this day, one of the key role models of my life and inspirations for my career. She was one of the strongest people that I know, having successfully overcome countless hurdles and challenges that often face women and minorities, broken through cultural stigmas, and lived life on her own terms. When I was 12 years old, she passed away within ~6-7 months of being diagnosed with an extremely aggressive lung cancer. I knew from then on that I wanted my life to be devoted to somehow making a difference for people who have cancer. It was during my late high school and undergraduate years that I started to learn about the many things that I’m not so good at, while at the same time realizing the things that I am good at, which eventually led me to applying to biomedical research graduate programs. On the first day of graduate school, my UCSD department chair, Dr. Mark Kamps, welcomed all the first-year students and told us we had all been hand-picked for the program because we are all weird. That we all think in out-of-the-box ways. I knew then that I was on the right track.

What was your greatest inspiration or challenge during your research training?

Although the inspiration to study cancer was initiated with my grandmother, I continued to be inspired by cancer patients that I encountered during my training. I was fortunate to have had the opportunity to rotate at the UCSD Moores Cancer Center during my graduate studies as part of the Howard Hughes Med-Into-Grad training program, where basic research graduate students could shadow clinicians over a few months. Seeing cancer patients bravely facing their diseases and undergoing treatments that are directly impacted by basic research—and directly seeing clinical needs—motivated me to continue my pursuit of biomedical research. This motivation ultimately is how I ended up at the H. Lee Moffitt Cancer Center and Research Institute. I knew that in order to try to make a difference for patients by conducting the type of translational research that I wanted to do, I needed to open my laboratory in a place that merges basic research and clinical expertise, where we could easily collaborate with clinicians. Moffitt has been an excellent environment for this.

You recently started your own lab at Moffitt Cancer Center, what has been your biggest challenge or inspiration as you moved in to this position?

In recently opening my lab, I think that the challenges that I have faced are nothing out of the ordinary in terms of the junior faculty learning curve and included the following: learning a new institutional infrastructure and non-lab bench duties/responsibilities that one is not necessarily familiar with as a postdoctoral fellow, applying for grants at a faster pace than I did as a postdoctoral fellow, coordinating laboratory finances, teaching graduate classes, mentoring my laboratory team members (at this time, one postdoc and one PhD student) on their projects (all while still conducting my own experiments for other projects). I think the biggest challenge in all of these efforts is finding the time to accomplish everything successfully; there are not nearly enough hours per day. In this regard, I have really come to appreciate and respect my previous and current faculty mentors—for being able to do so many things at the same time and to do them well. Oh, there was one more challenge: leaving California. That was really hard…

As for research inspiration, it has and always will be the patients. On the occasions that I have been able to speak with patients at Moffitt, their courage in the face of cancer continues to amaze me. My office window overlooks one of two main patient entrances and parking valets to the Moffitt Cancer Center hospital. Seeing the unending flux of cancer patients coming and going from the hospital all day long has been a huge motivating factor to keep me focused on making sure that our research is as clinically relevant and insightful as possible.

The Australian Melanoma Genome Project

Written By: Peter Johansson, Antonia Pritchard and Nick Hayward

QIMR Berghofer Medical Research Institute, Brisbane Australia

The Australian Melanoma Genome Project (AMGP) is the largest melanoma research effort ever undertaken in Australia. It is led by Melanoma Institute Australia (Sydney) and QIMR Berghofer Medical Research Institute (Brisbane) and comprises a national coalition of seven research sites and Bioplatforms Australia. AMGP was launched in 2012 with the aim to comprehensively analyse matched germline and tumour samples to identify common genetic aberrations that drive different histotypes of melanoma. The recent publication in Nature (doi: 10.1038/nature22071) describes the first large scale whole genome sequencing analysis of cutaneous, acral and mucosal melanomas. Almost 14,000 Australians are expected to be diagnosed with melanoma in 2017; of these, 2-3% will be diagnosed with acral or mucosal melanoma. The incidence of acral and mucosal melanoma is equal among people of different ethnic backgrounds, but account for most melanomas in dark-skinned populations.

The most significantly mutated genes include BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, KIT, MAP2K2, NRAS and NF1 in acral melanoma and SF3B1 and GNAQ in mucosal melanoma – the latter genes are commonly mutated in uveal but not cutaneous melanoma. In contrast to cutaneous melanomas, no acral or mucosal melanomas had variants in TP53, PTEN, RAC1, RB1, RASA2, DDX3X or PPP6C; and KIT mutations were more frequent in the latter histotypes, indicating that the molecular pathways driving each of the melanoma subtypes differ markedly.

As previously reported, mutations affecting the TERT promoter were very frequent in cutaneous melanoma, but were far rarer in acral and mucosal tumours (86% vs. 11%). Relative telomere length varied widely between the samples, ranging from six-fold shorter to ten-fold longer than the matched normal sample for each patient. Differences in telomere length did not correlate with histotype, but presence of the hotspot TERT promoter mutations was associated with shorter telomeres. Other than TERT, recurrent promoter mutations were observed in NFKBIE and RNF185, and in the 5’UTR of RPS27, PES1, RPS14, CHCHD2 and MRPS31 in cutaneous melanomas; these were not observed in acral or mucosal histotypes. In addition to mutations, structural variants contributed to the overall aberration frequency in key driver genes, particularly NF1, TP53, PTEN, KIT (and adjacent PDGFRA), BRAF (and adjacent MET) and MITF; additionally, acral and mucosal melanomas had frequent amplifications of CCND1. Structural variants were significantly more common in acral and mucosal melanoma than cutaneous melanoma, whereas the mutational landscape of the latter subtype was dominated by single nucleotide variants resulting from UV radiation exposure.

This study concluded that all melanoma subtypes were dominated by alterations to the MAPK, PI3K and RTK pathways. Importantly, nearly all of the cutaneous (99%) and the majority of the non-cutaneous (91%) melanomas harboured variants in one or more genes that could possibly confer sensitivity to an agent approved by the USA FDA, or are currently in a cancer clinical trial.

SMR Member News

Congratulations to Dr. William Harbour (Sylvester Comprehensive Cancer Center and the Bascom Palmer Eye Institute of the University of Miami Miller School of Medicine) for receiving a five year $2.5 million NCI grant entitled “Molecular predictive testing in ocular melanoma”. Under the five year grant, Harbour and his team will work toward developing highly accurate prognostic tests for ocular melanoma to improve patient survival. The collaborative trial will involve 30 centers in the U.S. and Canada.

Congratulations to Dr. Mandi Murph (College of Pharmacy, University of Georgia) and Dr. William J Hardman III (Department of Pathology at the Medical College of Georgia, USA) who have recently received a National Cancer Institute of the National Institutes of Health award for their continued research into the molecular mechanisms explaining premalignant changes in the etiology of melanoma.

Congratulations to Dr. Rizwan Haq (Dana-Farber Cancer Institute) for receiving the Stand Up to Cancer Innovative Research Grant for his project entitled “Identifying ad Targeting Mechanisms of Resistance to Immunotherapy”.

Congratulations to Dr. Anja Bosserhoff who was elected into the German Council of Science and Humanities (Wissenschaftsrat). It is the highest committee in Germany which advises the government.

Congratulations to Dr. Jennifer Leigh McQuade for receiving a 2017 ASCO/CCF Career Development Award for her project entitled “Clinical, molecular, and immunological significance of obesity in melanoma”.

Congratulations to Dr. Jennifer Wargo (MD Anderson) for receiving the Stand Up to Cancer Innovative Research Grant for her project entitled “Delineating the role of the microbiome in modulating tumor and host immunity”.

Congratulations to Dr. Richard White (Memorial Sloan-Kettering Cancer Center) for winning the Pershing Square Sohn Prize for Young Investigators in Cancer research. His research will continue to explore the role of adipocytes in promoting melanoma progression and metastasis in order to reveal new therapeutic targets.

The recent round of MRA grants totaling over $8.5 million awarded this year will support 34 melanoma researchers in six countries. Below are the grants which were awarded to SMR members:

Congratulations to Dr. Richard Carvajal (Columbia University) for winning the MRA Established Investigator Academic-Industry Partnership Award for his project entitled “An international prospective natural history study in uveal melanoma”.

Congratulations to Dr. Boris Bastian (University of California, San Fransisco) for winning the Melanoma Research Alliance Established Investigator Award for his project entitled “DNA based biomarkers for melanoma diagnosis and prognostication”.

Congratulations to Dr. Ze’ev Ronai (Technion Israel Institute of Technology) for winning the Melanoma Research Alliance Established Investigator Award for his project entitled “Advancing sbi-756, a translation inhibitor, for melanoma therapy.

Congratulations to Dr. Mark Shackleton (The University of Melbourne) for winning the Melanoma Research Alliance Pilot Award for his project entitled “Dissecting the significance of pigment heterogeneity in cutaneous melanoma”.

Congratulations to Dr. Rizwan Haq (Dana-Farber Cancer Institute) for winning the Melanoma Alliance Young Investigator Award for his project entitled “Biomarker-based application of anti-apoptotic inhibitors in melanoma”.

Congratulations to Dr. Lawrence Kwong (University of Texas M.D. Anderson Cancer Center) for winning the Melanoma Research Alliance Young Investigator Award for his project entitled PKCalpha as a node to overcome intrinsic mek inhibitor resistance in melanoma”.

Congratulations to Dr. Feng Liu-Smith (University of California, Irvine) for winning the Melanoma Research Alliance Young Investigator Award for his project entitled PKCalpha as a node to overcome intrinsic mek inhibitor resistance in melanoma”.

We want to hear from you! Please let us know if you or someone you know has received a grant, award, or promotion. We would like to share the news with the melanoma research community.

SMR Abstract Deadline: Fast Approaching

SMR is now accepting abstract submissions for the 9th World Congress of Melanoma - a joint meeting with the Society for Melanoma Research!

October 18-21, 2017 | Brisbane, Australia

Abstract Submission Deadline: June 12, 2017 at 11:59pm EST.

Late Breaking Abstract Submission will open June 13, 2017.