DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted May 23, 2019

Susan Gilmour, Ph.D., Lankenau Institute for Medical Research
FY15 PRCRP Idea Award with Special Focus

Susan Gilmour, Ph.D., Lankenau Institute for Medical Research
Dr. Susan Gilmour

Half of all melanoma tumors have mutations in the oncogene BRAF, which is responsible for promoting uncontrolled proliferation. BRAF inhibitors elicit rapid anti-tumor responses in patients with BRAF mutations, but the majority of patients develop resistance within months of the treatment. Therefore, it is necessary to keep developing drugs for melanoma patients. One strategy is to target other molecules in the tumors that are helping to sustain aberrant proliferation. Dr. Susan Gilmour, with a FY15 Idea Award with Special Focus, is investigating the ability to target polyamines in BRAF inhibitor resistant melanoma.

Polyamines are small ubiquitous molecules known to play roles in cell growth and proliferation. In particular, melanoma tumors have very high levels of polyamines compared to normal tissue.  Polyamines may be endogenously synthesized by cells or taken up by an active transport system. If the biosynthesis of polyamines is inhibited, then cells uptake polyamines from the environment to ensure survival. Dr. Gilmour aims to exploit the elevated activity of the polyamine transport system (PTS) in melanoma cells using a novel cytotoxic arylpolyamine (AP) drug.1 BRAF mutant melanoma cells have higher PTS activity and are more sensitive to AP compared to BRAF wild type cells. In order to enhance the tumor cytotoxic effect of AP, endogenous polyamine biosynthesis must be blocked. Difluoromethylornithine (DFMO) inhibits the major enzyme ornithine decarboxylase from converting ornithine to putrescine, the first polyamine in the synthesis cascade. Cells compensate for the loss of polyamine biosynthesis resource by increasing the activity of PTS to import extracellular polyamines.  This strategy makes BRAF mutant melanoma cells even more sensitive to AP.

Melanoma-bearing mice were next treated with AP and DFMO. The animal studies confirmed the in vitro data that treatment with DFMO and AP results in increased PTS activity in BRAF mutant melanoma, greater accumulation of AP in tumor cells, and increased tumor death. A combination treatment of BRAF inhibitor (PLX4720), DFMO, and AP resulted in a decrease in tumors without any adverse side effects and significantly delayed the recurrence of tumors. Additionally, treatment with AP and DFMO reduced the number of tumor infiltrating suppressive immune cells. Dr. Gilmour’s approach to targeting polyamines in melanoma represents a potential new therapy for melanoma patients to prevent relapse and improve survival.

Reference:

1 Peters MC, Minton A, Phanstiel Iv O, Gilmour SK. 2018. A novel polyamine-targeted therapy for BRAF mutant melanoma tumors. Med Sci. Jan 5:6. doi: 10.3390/medsci6010003.

Link:

Public and Technical Abstracts:  Targeting Increased Polyamine Transport of Resistant Melanomas

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Last updated Thursday, May 23, 2019