MRF 25th Anniversary: Melanoma Field Needs a Pipeline of Talented Young Scientists

In honor of the MRF’s 25th Anniversary, we share a guest blog post from Keiran Smalley, PhD, a previous MRF Career Development Award recipient and current MRF Grant Scientific Research Officer: 

I was invited to write something for this blog sharing my experience of how funding from the Melanoma Research Foundation (MRF) helps to bring impactful new discoveries to melanoma patients. I would like to share my own story of how a first grant from the MRF allowed my lab to pursue a line of research that helped bring a new treatment combination into the clinic.

Any vibrant field of human endeavor, whether it be in the arts, business or science, needs a pipeline of new talent in order to thrive. There are of course many ways to “prime the pump,” the most effective of these being the provision of financial support to promising young investigators, allowing them to get their research programs off the ground. Success of course breeds success, and the timely awarding of research grants to researchers early in their careers encourages them to stay in the melanoma field. It also, perhaps more critically, helps to persuade the reviewers of Federal grants that this candidate is worth taking a gamble on.

This point cannot be overstated enough. Reviewers for the National Institutes of Health (who pay most of our bills in academic science) are notoriously conservative and tend to be squeamish about supporting newly hired scientists with no grants or few scientific papers under their belt. Instead, they prefer to fund the older, established scientists who may not be as willing to push the envelope as much. I think this is where the MRF and its career-development granting mechanism has proven to be so effective, and it is abundantly clear that the award of a first MRF grant has led to some of the best scientific talent staying in the melanoma field.

In preparing for this blog post I took a quick look through the history of individuals who received career awards from the MRF over the years and it really is an impressive run down of individuals who went on to be eminent and established scientists who made a real impact in melanoma research. My story as a new investigator began in 2008 when I applied for an MRF Career Development Award. It was the first independent grant I had ever written and at the time I didn’t quite have my own lab but was sitting on a job offer at the Moffitt Cancer Center.

The application that I submitted was focused on discovering new strategies to improve responses to BRAF inhibitors, with the goal of delivering new and better drug combinations to melanoma patients. Once my new lab was started at the Moffitt Cancer Center in Tampa, we quickly got to work on the problem of BRAF inhibitor resistance. Meanwhile in the clinic, the initial trials of the BRAF inhibitor vemurafenib were already underway and looking very promising.

We rapidly realized that treating the melanoma cells with BRAF inhibitors caused them to find new ways to keep growing, often by re-activating the same BRAF-driven growth pathway the BRAF inhibitors were targeted against. We discovered that adding a second drug (the MEK inhibitor) improved the activity of the BRAF inhibitor by strongly shutting this growth pathway down, killing the melanoma cells. These findings, which first demonstrated the utility of combining a BRAF inhibitor with a MEK inhibitor were published in 2010, about one year after our MRF grant had started.

In August of 2010, the results of the first phase I clinical trial of the BRAF inhibitor vemurafenib were published in the New England Journal of Medicine. This trial was a roaring success, with incredible initial responses seen in most patients with BRAF mutant melanoma, and it seemed that a corner had been turned in improving melanoma therapy.

Dr. Vernon Sondak (also from Moffitt Cancer Center) and myself were asked to write the accompanying editorial in the New England Journal of Medicine outlining the importance of the BRAF inhibitor trial. When it became clear that single agent BRAF inhibitor therapy led to impressive levels of response followed by drug resistance after about six months, clinical trials were initiated to test the BRAF-MEK inhibitor combination that we had suggested in our work supported by our MRF grant. This new combination proved to be much more successful than single agent BRAF inhibitor therapy, pushing up response rates and decreasing side effects.

At the last analysis, over 30% of patients with stage IV melanoma who received the BRAF-MEK inhibitor combination were still alive and doing well after five years. This combination, which was FDA-approved for BRAF-mutant metastatic melanoma in 2014, has now become a standard of care therapy.

It has been an honor to play a small part in this amazing story that has revolutionized the treatment of what was once seen as a uniformly deadly disease. Since this time, my lab has continued to work on drug resistance in melanoma, as well as broadening our portfolio into the study of rare melanomas (such as acral, uveal and pediatric melanoma). At this time, we are really interested in determining the best ways to use immunotherapy and targeted therapy in sequences that improve responses while limiting side effects. My initial success in getting the MRF grant seemed to have impressed some NIH reviewers too (!), and I was able to secure NIH funding for many of my projects.

These days I get to see the MRF grants process from the other side as the MRF Grant Scientific Research Officer. It really is exciting to see the new crop of bright young scientists coming up through the ranks, and I am always so impressed by all of the great new ideas they have on how to beat this dreadful disease. It fills me with a great deal of hope for the future, and I think by continuing to support the MRF grants program we can attract the best young minds and encourage them to focus their careers on finding new treatments and cures that will improve the lives of melanoma patients.

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