Preventing Melanoma Progression by Targeting Nonclassical Androgen Signaling
Abstract
The Principal Investigator’s potential in melanoma research: Todd Ridky, M.D., Ph.D., is a dermatologist physician scientist with significant expertise in melanocyte and melanoma pathobiology, cell signaling, and sex differences in cancer. A large portion of melanoma arises from preexisting benign moles. Dr. Ridky’s group is the only one to have successfully modeled this progression using primary BRAF(V600E) melanocytes isolated from actual human moles. They were the first group to define a role for the nonclassical sex steroid receptors GPER and PAQR7 in melanocytes, and have successfully translated these basic science discoveries into a recent phase 1 human trial testing a new agent with a novel mechanism of action against a previously undrugged target for melanoma and other advanced cancers (NCT04130516). Dr. Ridky is emerging as a leader in translating seminal basic science discoveries to people, and he has the potential for a highly impactful career at the forefront of melanoma research. Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Areas: This proposal is designed to understand how male sex hormones affect melanoma, and therefore, addresses the focus area “Prevention of Melanoma Initiation Factors.” This proposal explores the idea that testosterone promotes melanoma by activating a protein in melanoma cells called ZIP9. There are no approved drugs that were designed to target ZIP9; however, we believe that ZIP9 is eminently druggable in melanoma tumors and can be blocked by drugs already approved for prostate cancer. Thus, our proposal also addresses the FY20 MRP Focus Area “Therapeutic Prevention.” Scientific Objectives and Rationale: Melanoma is associated with exposure to solar ultraviolet radiation, and disproportionally affects males, with incidence and mortality in the United States being 1.4 times and 2.1 times higher, respectively, in males vs. females. Military personnel often spend significant time outdoors, are 80% male across all branches, and are therefore at especially high melanoma risk. The consistently higher melanoma burden in males has been appreciated every year since at least 1969, and parallels sex-associated differences in many other cancer types where males typically have worse outcomes than females. We have strong preliminary data from our lab showing that increased melanoma burden in males results from far more than just differences in environmental exposure to sunlight. For example, in laboratory mice housed inside, melanomas grow much more aggressively in male mice than in female mice in the adjacent housing cage. Our findings suggest that the male hormone testosterone is responsible for much of this difference. While testosterone is well known to affect the growth of prostate cancer, and the mechanisms for that are relatively well defined, testosterone seems to affect melanoma through completely different pathways. Our pilot studies show that the testosterone effects in melanoma result from testosterone binding to a protein in melanoma cells called ZIP9, which was first discovered as a transport protein for zinc. There are no drugs that were designed to target ZIP9; however, we discovered that drugs approved for prostate cancer do inhibit ZIP9 in melanoma, and inhibit the growth of melanomas in male mice. Interestingly, these drugs had little effect on melanomas in female mice. We propose conducting preclinical efficacy studies in mice that would likely support an FDA application for a new trial testing the utility of repurposing a well-tolerated and already approved prostate cancer drug called apalutamide for melanoma. Because apalutamide is routinely used in people, is widely available, and is generally safe and well tolerated, this proposal has the potential to rapidly translate to new melanoma trials. Ultimate Applicability of This Research: Because testosterone levels are much higher in males than in females, we anticipate that drugs that inhibit ZIP9 woul
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110860
Entities
People
- Todd Ridky
Organizations
- United States Army
- University of Pennsylvania