Genetic characterization of therapeutic resistance in cutaneous melanoma

Melanoma, the deadliest form of skin cancer, will be diagnosed in over 70,000 people in the United States this year. This cancer commonly presents in sun exposed areas of the body. Some melanoma lesions can be removed with surgery, while more advanced disease requires drug treatments. Currently, drug treatments are based on DNA alterations identified during initial evaluation. Approximately half of all patients with melanoma have the same DNA alteration, a specific mutation that activates tumor growth. This mutation can be targeted with current drug treatments to reduce aberrant growth. Although most patients initially respond to this treatment, a large percentage of patients will relapse within a few months. In some patients we do not understand why treatments fail.

Our research has focused on understanding why patients relapse from melanoma therapies and identifying alternative therapies to manage disease. To do this, we have employed cancer cell and mouse models in which melanoma can be studied outside of the patient. We utilize an approach referred to as Sleeping Beauty, which forces cancer to show us how it evolves to reactivate tumor growth while on drug. To better understand what causes drug resistance, we have created a new technology that allows us to exam cancer down to a single cell. This approach gives us the ability to view complex interactions that promote resistance to drug treatments. In mouse model of melanoma drug resistance, we were able to identify genetic alterations that cooperate to overcome drug inhibition. Additionally, drug resistant melanomas show traits that are absent in normal cells. We are working to exploit these traits using alternative therapies, such as using Vitamin C, in doses only achievable through medical professionals. Doses at these high concentrations can be toxic to some drug resistant cancer cells and may be an alternative medicine to combat melanomas.

Although we have made significant advancements in treating patients with melanoma, there is an immediate need to advance our understanding as to how drug resistance develops. By engineering new technologies to analyze cancer down to a single cell, understanding commonalities in drug resistant cell populations, and creating new treatment regimens, we are prepared to advance medicine and impact the lives of patients with melanoma.