Strides and Obstacles in Melanoma Research Spotlight on Martin McMahon, PhD
Like so many in the melanoma research field, Martin McMahon, PhD, Huntsman Cancer Institute’s senior director of pre-clinical translation and Professor at the University of Utah, entered the melanoma field by accident. As a postdoctoral fellow he began working on a family of molecules involved in intracellular signaling called RAF. After the Sanger Center in the UK identified one of the molecules McMahon studied — BRAF, as being a major driver of a subset, that is 50% of all human melanomas, the trajectory of his career shifted. “I went from being interested in biochemistry, then cell and molecular biology, and then ultimately, genetically engineered mouse models to a very specific interest in melanoma as a disease,” says McMahon. Genes he and others were studying ended up being key to melanoma research and developing an understanding that targeting enzymes with drugs could, in principle, give rise to new therapies for melanoma treatment.
The field’s expansion occurred at a rapid pace, as trained dermatologists and researchers in immunology and immunotherapy jumped into the field. But what has been most astounding is the impact melanoma research has had on the entire field of cancer research over the course of a decade. From dermatologists who develop an interest in melanoma to researchers interested in immunology— (realizing immunotherapy in melanoma has become a poster child for how immunotherapy can be made to work), and others studying signal transduction pathways relevant to melanoma, the field has drawn individuals with diverse interests and expertise at a particularly pivotal time. According to McMahon, the past decade has demonstrated how a basic understanding of melanoma, the immune system and how viruses work can be translated into effective therapies for a disease that was previously incredibly difficult to treat. McMahon estimates the needle has moved nearly 180 degrees from where it stood 10 years ago. He recalls when the melanoma research field was segregated between believers in vaccine-based approaches, cell transplantation approaches and chemotherapy approaches, giving the field an air of disunity.
In 2011, with the FDA approval of two new drugs, ipilimumab, an immunotherapy, and vemurafenib, a targeted therapy, in one year, came a sudden validation of the approaches of two groups of melanoma researchers. The approval of ipilimumab was a validation of those believing one could mobilize the immune system to attack and kill melanoma. The approval of vemurafenib was a validation of people believing, “if we understand melanoma, and its genetics and biochemistry in more depth, we can develop better chemotherapies to target specific vulnerabilities unique to melanoma,” explains McMahon. He says the success of two varied approaches to treating advanced melanoma united the field in a meaningful way.
What further galvanized the field, says McMahon, was increased collaboration and a focus on combinatorial therapy — the way researchers think melanoma and other cancers will be conquered. But, opportunities for combinatorial therapies also involve differing perspectives. “One therapy comes from the world of immunology and another from the world of genetics and biochemistry,” says McMahon. “If you want to think about meaningful ways to combine them, it’s necessary to get immunologists and cancer scientists and geneticists and biochemists to talk to one another.”
McMahon claims that as a cancer geneticist and biochemist, he knows enough about immunology to be dangerous, but not enough to intelligently advise on clinical trials. His research is facilitated by experts in immunology who can guide him about approaching next steps in preclinical models he works with. As a PhD, McMahon doesn’t conduct clinical trials, but at Huntsman he has the opportunity to work alongside people who do. His voice is heard among colleagues in the context of thinking about how to design those trials and what may be the right way to combine different agents. His laboratory experiments reveal much about combining immunotherapy and targeted agents with the understanding of how to minimize toxicity and maximize therapeutic benefit.
Though in the early stages in combining agents, there is a sense of optimism due to the availability of multiple agents active in combatting melanoma. But what McMahon believes is most important in advancing the research is having a sense in the field that people from different areas can come together to discuss options in a substantive and meaningful way that can be translated into real clinical trials activity. McMahon explains that melanoma has gone from being a backwater of oncologists whose clinical trials routinely failed to now being a poster child in cancer for targeted agents, immunotherapy, and even virus-based therapies. Such massive strides in collaboration and shared knowledge has helped advance melanoma research to the premier level that now exists. McMahon says it’s a message of optimism in the melanoma story for the past ten years that demonstrates going from a place of little hope to a more promising place due to a greater understanding of genetics, biochemistry, the immune miro-environment and other elements of a disease that can turn into effective therapeutic interventions.
Beyond ensuring collaboration, McMahon believes the biggest obstacle to advancing the field is a lack of support for research at a federal level, all the more so in the light of the president’s proposal to slash the NCI budget by 20 percent. Though funding from the Melanoma Research Alliance (MRA) and like-minded organizations helps sustain a great number of researchers, he stresses that stagnation has existed for the NCI budget over the past 16 years, creating an historically long period of funding stasis. The NIH budget showed a marked decrease following a period of stasis during Bush’s presidency. If not for philanthropic organizations like MRA and others that specifically fund melanoma, the field likely would not have sustained the level of research that now exists. McMahon claims that though there is no substitute for NCI/NIH grants, it’s vital that an organization like MRA continue to fund more preliminary or proof of concept work that hopefully will then become funded by an NIH grant once the PI acquires sufficient preliminary data. The federal government can potentially step up to make them a five-year grant with a 1 to 2 million-dollar budget. “It’s a problem that extends beyond melanoma research. Stagnancy in funding levels of the NIH and the NCI is occurring precisely at a time when cancer scientists and oncologists are excited about having so many new opportunities, to treat not just melanoma but other cancers as well,” says McMahon.
Another source of frustration McMahon underscores is the impact of underfunding for young and upcoming scientists. Over the past 16 years, students and postdoctoral fellows have seen their mentors struggling to preserve sufficient funding to keep their labs open. One effect of this is that many trainees are choosing to leave academic science, preferring to not have to secure one grant after another to sustain their career. McMahon fears the loss of a substantial number of young individuals who may have, through the academic world of science, contributed to cancer research and cancer therapeutics. He says fortunately, MRA’s Young Investigator Awards have an important sustaining influence on this generation of researchers. To date, MRA has funded 101 Young Investigators.
McMahon considers MRA’s funding an anchor for all researchers in melanoma, something crucial at a time when universities lean heavily toward a soft money model. He explains that without the support of MRA dollars, the burden for ensuring sustained, essential research would rely entirely on government support, falling well short of what is needed.
McMahon contends, “If we underinvest in an area where we have an enormous lead right now, the consequences will have a far reaching impact on not just melanoma, but the entire field of cancer research, including the biotechnology and pharmaceutical industry that is essential for translating cancer research into new therapeutics.”
BRAF FDA NIH targeted therapy Immunotherapy ipilimumab Grants