Melanoma, It’s Not All Written in the Genes 

It is well established that some cancer risk factors are interconnected to genetics or other unchangeable factors, such as age or gender. We also know that external factors, such as sun exposure, increase one’s risk of developing melanoma. It’s now emerging how important other external aspects – related to our lifestyle – are for melanoma survival and response to therapy.

During the third annual Noreen O’Neill Melanoma Research Symposium at Wistar, speakers discussed inflammation, certain medications, vitamin D levels, obesity, and the bugs that populate our gut as potential modifiers of patients’ survival and outcome from targeted and immune therapies.

The Symposium, made possible through the Noreen O’Neill Melanoma Research Fund and supported by the Melanoma Research Alliance and the Melanoma Research Foundation, attracts a world class line up of speakers and has become a regular appointment for melanoma experts to come together and collectively discuss how melanoma research is advancing.

With its rates on the rise, it was estimated by the American Cancer Society that melanoma will strike 96,480 Americans in 2019. The research community has made giant leaps forward in the past decades with targeted and immune therapies that have brought tangible improvements in survival of patients for whom almost no hope was available before.

Yet, there is still a long way ahead to defeat the disease. And, as it often happens, when major advances hit the clinic, basic researchers are already working behind the scenes finetuning next steps, tackling drawbacks and figuring out the reasons for failure.

Melanoma is a highly-diverse disease. Within the same tumor, multiple cell populations exist that impact tumor growth and sensitivity to therapy differently. To further complicate the picture, melanoma cells change their characteristics over time or in response to therapy.

This complex aspect of the disease was the main theme of the Symposium.

Delving into the Science

Speaker Jean-Christophe Marine, Ph.D., professor and director of the VIB-KU Leuven Leuven Center for Cancer Biology, Belgium, discussed the adaptive ability of melanoma cells as the origin of therapy resistance.

Relapse after therapy is driven by a small number of cells that remain alive upon drug exposure while the bulk of the tumor is killed. This status is known as minimal residual disease. Drug tolerance is acquired by these cells through genetic mutations and, as recently discovered, non-genetic mechanisms that allow them to quickly adapt and survive.

Marine postulated that “single cell approaches” for tracking and isolating single residual cancer cells are the most effective way to tackle melanoma cell diversity. Such approaches allowed his laboratory to hunt for vulnerabilities of these cells that can be exploited to enhance therapy.

Martin McMahon, Ph.D., professor of cancer biology and senior director for preclinical translation at the University of Utah, discussed his most recent findings that explain why certain targeted therapies that were originally predicted to be the holy grail for melanoma failed to deliver clinical benefits.

According to McMahon’s results, one of these drugs called trametinib activates a particular process called autophagy, which allows the cells to recycle their building blocks and sustain survival.

Based on this discovery, a clinical trial is about to begin that combines trametinib with a drug that blocks the autophagy process. The researchers will evaluate if this drug combination can enhance the antitumor effects of trametinib in melanoma patients.

Research presented by Jennifer McQuade, M.D., assistant professor and physician scientist at MD Anderson Cancer Center, focuses on patient factors that contribute to shaping immunity and response to immunotherapy.

She discussed the obesity paradox in melanoma. This is the observation that obesity – well-established as a risk factor for several cancer types – predisposes to melanoma but is associated with better outcomes in response to immune and targeted therapies.

McQuade also spoke about the role of the microbiome (bacteria that populate our gut) in affecting therapy response. As less than 10% of the microbiome composition is determined by the host’s genetic makeup, and diet, environment and medications are major components, the microbiome is an external factor that can be modified with diet.

In fact, studies have shown that melanoma patients whose diet is high in fiber respond better to immunotherapy, while over-the-counter probiotics are associated with lower microbiome diversity.

To establish if diet intervention can influence outcomes in immunotherapy, McQuade’s team at MD Anderson is conducting rigorously controlled clinical trials in which melanoma patients undergoing immunotherapy also receive high-fiber diet.

On a similar theme, Julia Newton-Bishop, Ph.D., professor at the University of Leeds, U.K., reported evidence for a number of host factors and environmental exposures that modify the tumor microenvironment and influence melanoma survival, including systemic inflammation, which might be therapeutically controlled, smoking and vitamin D levels.

Wistar’s Meenhard Herlyn, D.V.M., D.Sc., director of the Melanoma Research Center and professor in the Molecular and Cellular Oncogenesis Program, took the audience on a historical journey through the different stages and accomplishments of melanoma research, from the era of monoclonal antibodies, believed to be “magic bullets” that would cure cancer, through the discovery of the genetic basis of melanoma and the causative effect of gene mutations, to immunology studies.

Despite those accomplishments, by the early 2000s, Herlyn said, it seemed like nothing worked. Then, the modern era of melanoma research began with the discovery of targeted therapies and, since then, giant leaps have been made.

A pioneer and witness to how the field has expanded, Herlyn has made important contributions to all those stages. He showed an overview of the many experimental models his laboratory has developed over the years, starting with melanoma cell lines, through 3-D skin reconstructs, to latest efforts in the creation of a patient-derived xenograft collection for preclinical drug testing, and “humanized mice”, in which the human immune system is rebuilt in a mouse. These powerful models have allowed the Herlyn lab and many other laboratories around the world to make important discoveries, and continue to be unique tools to advance melanoma research.

Closing the Symposium, Wistar’s Jessie Villanueva, Ph.D., associate professor in the Molecular and Cellular Oncogenesis Program, invited everyone back to Wistar in 2020 with their next breakthroughs in melanoma research.