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MC1R-selective small melanocortin analogs for melanoma prevention

Zalfa Abdel-Malek, PhD

Award Type Established Investigator Award
Institution University of Cincinnati
Donor Support In Memory of John N. Decker
Description:

Melanoma is the deadliest form of skin cancer, and despite the exciting advancements in treatment, there is still no cure for late stage disease. The incidence of melanoma continues to rise, particularly in young adults. Therefore, there is an urgent need to develop effective melanoma prevention strategies that will reduce the morbidity and mortality associated with this aggressive tumor. Sun exposure is a main causal factor for melanoma, and skin pigmentation and DNA repair capacity are important determinants for melanoma risk. We propose to develop a melanoma chemoprevention strategy based on targeting the melanocortin 1 receptor (MC1R), a major regulator of pigmentation and DNA repair in melanocytes, the precursors of melanoma. Expression of loss-of-function variants of the MC1R gene is strongly associated with red hair, fair skin, poor tanning, and increased risk for melanoma. More than 24% of all melanoma patients are carriers of a loss-of-function MC1R variant. Additionally, almost 50% of the White population of the U.S.A. are carriers of one of many MC1R variants, which predisposes them to melanoma. These statistics underscore the significance of this gene as a melanoma susceptibility gene. We have developed small peptide analogs of a-melanocyte stimulating hormone (a-MSH), the physiological agonist of the MC1R. These peptides mimic a-MSH in enhancing repair of ultraviolet radiation (UV)-induced DNA damage, and stimulating pigmentation in human melanocytes in the absence of any UV exposure. Our peptides are unique in their high selectivity for MC1R, which should reduce any off target effects. We propose to develop these peptides in a topical formulation, and to test their efficacy in stimulating pigmentation and reducing UV-induced DNA damage in cultured human skin substitutes in vitro and in vivo. The translational outcome of this project, which is based on compelling and extensive data that we have generated, will have a huge impact on melanoma prevention in millions worldwide with high risk for melanoma, particularly those who are carriers of MC1R variants and/or mutations in other melanoma predisposition genes, such as CDKN2A (p16).