Denver skin cancer conference explores breakthroughs in melanoma research

Neil Box, PhD, oversees the morning plenary session at IPCC 2017

Early this week, Denver hosted the International Pigment Cell Conference 2017, a gathering of researchers exploring current directions in the science and treatment of skin cancers including melanoma. In addition to bringing together top minds in the field to encourage collaboration, the conference presented cutting-edge research and possible new treatments to combat this dangerous condition.

“Denver is a good place for this conference. Due to our altitude and outdoor lifestyle, skin cancer rates, and melanoma rates in particular, are higher than the national average. The research being presented this week has the real potential to help people with these cancers in Colorado and beyond,” says Neil Box, PhD, investigator at the University of Colorado Cancer Center, associate professor in the CU School of Medicine, and one of the conference organizers.

In fact, Colorado skin cancer rates are almost 12 percent higher than the national average, with 21.9 out of every 100,000 Coloradoans being diagnosed with some form of skin cancer every year. Skin cancer rates are even higher in Colorado communities at elevation; for example, residents of Pitkin County, which sits at an elevation over 8,000 feet, are diagnosed at a rate of 32.2 out of every 100,000 people per year.

Tuesday morning’s plenary session, titled Breakthroughs in Melanoma Research, explored developing options for patients with this most dangerous form of skin cancer. The background is that many new therapies exist targeting melanoma, some recruiting elements of the immune system to attack cancer and others directly targeting the genetic changes that make melanoma different than healthy cells. However, melanoma often evolves resistance to immunotherapies and targeted treatments, which eventually stop working. A major challenge addressed at the conference was optimizing the use of these new medicines to create prolonged control of the disease.

One piece of this challenge is knowing when a therapy has stopped working so that patients can switch as soon as possible to a new strategy that may offer additional control. Speaking on this topic, Richard Marais, PhD, director of the Cancer Research UK Manchester Institute and professor of Molecular Oncology at the University of Manchester, suggested that monitoring levels of tumor DNA circulating loose in blood could act as an early warning system that a therapy has reached the end of its effectiveness. Testing for circulating tumor DNA (ctDNA) requires only a simple blood draw, sometimes referred to as “liquid biopsy.”

“Circulating tumor DNA could help decide when to switch patients from one treatment to another. For example, we monitor ctDNA levels every two weeks and when the circulating tumor DNA reaches a certain level, we switch patients to a new therapy,” Marais says. Rather than waiting for visual evidence from a scan that a melanoma has restarted its growth, Marais suggests that monitoring levels of ctDNA could help patients stay ahead of cancer’s growth, switching to new therapies before and not after a melanoma has had a chance to increase its size after acquiring therapy resistance.

Another strategy may be to focus on eradicating a melanoma early in the course of treatment, giving the cancer no time to develop resistance.

“By the time we see a melanoma develop resistance, the horse has probably bolted. It may be better to prevent resistance by optimizing therapy up front,” says Grant McArthur, PhD, co-chair of Melanoma and Skin Service, and head of the Molecular Oncology Laboratory at Peter MacCallum Cancer Centre in Victoria, Australia.

One strategy McArthur suggests is combining therapies to concurrently target likely pathways of resistance instead of waiting for resistance to develop before targeting these pathways. McArthur also hopes to direct research at new genetic targets and signaling pathways that allow melanoma to develop resistance. One of these genetic changes is deactivation of the gene p53, a well-known tumor suppressor. Basically, McArthur says, deactivation of p53 is associated with the development of treatment resistance – most often, melanomas that have acquired resistance have mutated p53 (and/or related tumor suppressor gene pRB). Therapies targeting p53 deactivation have been a goal in many cancer types, and McArthur’s work shows the likely benefit of such therapies to preempt the development of treatment resistance in melanoma.

Another angle in addition to targeting a melanoma itself is to work with the changes that allow melanomas to gain footholds elsewhere in the body. Maria Soengas, PhD, head of the Melanoma Group at Centro Nacional de Investigaciones Oncologicas in Madrid, Spain, detailed her research into changes that take place in what is called the “premetastatic niche” that allows melanoma to spread. In short, there are tissue changes that precede the development of a metastasis, often the accumulation of aberrant immune cells and protein markers. These changes may prime sites to host new colonies of melanoma. Soengas detailed factors of the pre-metastatic niche that allow melanoma to spread and may in turn become targets for new therapies hoping to stop this spread.

Keiran Smalle, professor and director of the Melanoma and Skin Cancers Center of Excellence at Moffitt Cancer Center suggests that genetic changes are not the only mechanism of resistance in melanoma. In addition to evolution driven by genetic changes, Smalle’s research explores the epigenetic changes associated with melanoma. He calls this “phenotypic plasticity,” or the ability for cancers with the same genetics to look different.

“Our interest is in the early phase of adaptation of tumors on therapy,” Smalle said. Instead of exome sequencing, which shows the code of a cell’s genes, Smalle’s group approaches melanoma from the perspective of the proteins these genes produce. He finds that due to phosphorylation and other epigenetic changes, melanomas with the same genes may learn to express these genes differently, sometimes aiding the development of treatment resistance. One specific mechanism that Smalle hopes will see more research attention is the role of ephrin signaling, which he calls, “a key driver of adaptation.”

“It’s an absolutely exciting time for melanoma research,” says Neil Box. “We have all these new drugs and even new classes of drugs and now in addition to continuing the work of drug discovery, our challenge is to learn to better use the strategies we have in hand. We’re already extending patients’ lives with these drugs, but we know there’s so much more we can do.”

The conference in Denver this week puts a peg in treatments that work and looks to the future of medicines and strategies to treat and even cure this very Colorado condition.

About the author: Garth Sundem

In addition to writing for the University of Colorado Cancer Center, Garth is the author of the books The Geeks' Guide to World Domination, Brain Candy, and Geek Logik. Contact him at garth.sundem [at] ucdenver.edu.

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