Scientists on the SU2C-Cancer Research Institute Cancer Immunology Dream Team and the SU2C-Melanoma Research Institute Melanoma Dream Team have separately reported findings that provide new insights into melanoma, the deadliest form of skin cancer, and could help solve the puzzle of resistance to existing therapies and pave the way for development of new treatments.

Why It’s Important

More than 75,000 cases of melanoma, and more than 10,000 deaths, are reported in the United States every year. While it usually originates in the skin, melanoma can metastasize throughout the body. The new immunotherapy drugs are highly effective against melanoma in some cases. Former President Jimmy Carter had melanoma in his liver and brain; after surgery and radiation, he received pembrolizumab (Keytruda®), an immunotherapy that cleared up the remaining tumors, and he is cancer-free a year and a half after the treatment. However, immunotherapies are effective in only about 40 percent of cases, and scientists are trying to determine how to overcome resistance to the drugs.

Most melanomas occur on skin that is exposed to sunlight, but a form called acral lentiginous melanoma (ALM), occurs on the palms of the hands and soles of the feet, and under fingernails and toenails. ALM can be very aggressive, spreading rapidly to internal organs. ALM is relatively rare, but it is more likely to end in death than other types of melanoma. It is more common among people with dark complexions. The Jamaican musician Bob Marley died of ALM that originated under a toenail.

Immunology research: The SU2C-CRI Dream Team supported a study at the UCLA Jonsson Comprehensive Cancer Center by a team led by Antoni Ribas, MD, PhD, co-leader of the Dream Team (the UCLA group also included Roger S. Lo, MD, PhD, a 2011 SU2C Innovative Research Grant recipient, and Siwen Hu-Lieskovan, MD, PhD, recipient of a 2017 SU2C Phillip A. Sharp Award for Innovation in Collaboration). The research was based on earlier findings that people whose cancers contain genetic mutations in genes such as JAK1 and JAK2 will receive little or no benefit from pembrolizumab.

Over a period of two years, the scientists worked to understand how melanoma cells respond to interferon released by T cells. The response of the interferon gamma pathway – a complex set of chemical reactions – within the cell can cause immunotherapy to fail. They analyzed dozens of melanoma cells lines and tumor samples from patients and conducted tests with advanced technology called a lentivirus shRNA screen. The team discovered and mapped out the molecules involved in the pathway. Armed with this knowledge, this team or others can move forward to try to turn off the process so that immunotherapy will succeed more often in the battle against melanoma.

Genetic research: Scientists on the SU2C-MRA Dream Team set out to find genetic targets in acral lentiginous melanoma (ALM) the way the BRAF gene has provided a target for therapies in cutaneous melanoma, the much more prevalent form. Little is known about the genetic landscape of ALM.

They discovered that a protein called TERT – telomerase reverse transcriptase – is often genetically altered in ALM. TERT can encourage the rapid growth of cells that is characteristic of cancer. The team ran laboratory experiments with a drug that inhibits TERT. They found that more than 75 percent of cancer cells from patients with ALM were affected by the drug after only 72 hours.

“These findings provide insight into the role TERT plays in the formation of ALM, and reveal preliminary evidence that inhibiting TERT has a deadly effect on ALM cancer cells,” said Dream Team Leader Jeffrey M. Trent, PhD, president and research director of the Translational Genomics Research Institute (TGen) and one of three senior authors of the study.

“These data establish a foundation for understanding ALM’s genetic triggers, with the ultimate goal to inform ALM clinical management for patients,” added Jeffrey A. Sosman, MD, a melanoma expert at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and a co-senior author of the paper.

For more information:

The full text of “Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression” by Ribas and others, as published in Cell Reports, can be found at:
http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30525-9

The abstract of “Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma,” by Trent and others, can be found at:
http://genome.cshlp.org/content/27/4/524.abstract?sid=482f3a3d-38f0-49f2-82ae-dfc0ab39c25f

AACR, May 2017