Developing Rational Approaches for Acral Melanoma
Abstract
Our proposal addresses the fiscal year 2022 (FY22) Melanoma Research Program Challenge Statement by developing therapeutic strategies that can intercept progression of acral melanoma (AM). While new therapies have revolutionized the treatment of cutaneous melanoma, patients with rare but aggressive melanomas that develop in the hands, feet, or nails (collectively known as AM), respond poorly to current therapies. Therefore, effective treatments for AM patients are sorely needed. The overarching goal of this proposal is to develop effective treatments for AM, by perturbing lipid and redox metabolism as a therapeutic approach for AM. Melanoma is one of the fastest growing tumor types in the U.S., with higher incidence for military personnel than for the general population. While AM affects all world populations, it is the most common type of melanoma in ethnic groups and often occurs in older patients. Since greater than 40% of the Department of Defense personnel belong to racial and ethnic groups, a significant percentage of U.S. military members and Veterans are at risk for AM. Additionally, injuries in the hands and feet have been reported to increase the risk of AM. Because military personnel are more susceptible to suffer injuries of the feet or hands due to intense physical activity, militaries are vulnerable to AM. Unfortunately, AM is often diagnosed at advanced stages when tumors are generally more difficult to treat. Furthermore, drug targets for AM remain elusive and there are no effective treatments for patients with this type of cancer. Recent studies have found that 70% of AM have mutations in genes that lead to activation of a signaling pathway called MAPK. While drugs that inhibit the MAPK pathway (called MAPK inhibitors; MAPKi) have shown transient efficacy in cutaneous melanoma, these drugs have limited efficacy in AM. We discovered that melanomas resistant to MAPK inhibitors are dependent on a protein called S6 kinase 2 (S6K2). By studying the mechanism elicited by S6K2 inhibition, we have identified a unique approach to target this class of tumors. We found that inhibition of S6K2 triggers accumulation of polyunsaturated fatty acids (PUFAs) and increase in reactive oxygen species, which eventually cause cellular damage and melanoma cell death. We found that combining two drugs, which are used in humans, called fenofibrate and DHA (Omega-3), combats AM. Based on our previous studies, we postulate that AM harboring genetic alterations within the MAPK pathway are dependent on S6K2 and, therefore, S6K2 would constitute a promising therapeutic target for AM. In this application we propose to: Aim 1: Identify AMs that are dependent on S6K1/2. We will study the molecular consequences of inhibiting S6K1/2 in AM. We will also investigate the mechanism whereby S6K1/2 contributes to AM cell death. Aim 2: We will Evaluate the effect of combining FNB + DHA in various models derived from AM patients. These include tumor organoids’ which are miniaturized, and simplified tumors grown in vitro in three dimensions mimicking the in vivo behavior of AM. We also possess a large collection of mouse models harboring tumors derived from AM patients (AM Avatars) to determine the efficacy of our proposed combination therapies. These models are clinically annotated, are being molecularly characterized and include early and advance tumors, representing the spectrum of AM. We expect to identify effective therapies that can be translated into novel treatments for AM. We also expect to define markers to select patients that are most likely to respond to therapy and markers to monitor response to treatment. To achieve these goals, we have assembled a team of investigators with multidisciplinary expertise including experts in melanoma biology and preclinical evaluation of novel therapies, chemistry, structural biology, proteomics, computational biology, bioinformatics, and biostatistics. The expertise of t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310914
Entities
People
- Jessie Villanueva
Organizations
- United States Army
- Wistar Institute