Discovery of Alpha-MSH Analogs for Skin Cancer Prevention

皮肤癌，以黑色素瘤、基底细胞癌或鳞状细胞癌的形式出现，是最常见的 美国的癌症，主要是由太阳暴晒引起的，这会导致DNA损伤和 光致癌。越来越多的证据表明黑素皮质素1受体的重要性。 (MC1R)在人黑素细胞(HMC)及其内源性配体α-黑素细胞上表达 促黑激素(a-黑素皮质素；a-MSH)和促肾上腺皮质激素(ACTH)在光保护中的作用 对抗皮肤癌。首先，MC1R被其配体激活增加了 光保护真黑素，黑色素的一种黑褐色形式。第二，基因的功能缺失突变 人类MC1R基因与红发表型、晒黑能力差和皮肤风险增加有关 癌症。黑素皮质素前体阿片黑素皮质素原基因的某些突变也会导致 红发表型。第三，我们发现了a-MSH作为一种生存因子的新作用，它拯救了hMC。 紫外线(UVR&GT；)诱导细胞凋亡，减少DNA损伤。这些影响在以下方面不存在 HMC表达功能丧失的MC1R等位基因，表现出DNA修复能力降低。在此基础上 证据，这项建议的主要目标是开发一种新的皮肤癌预防策略，基于 利用可以局部给药的a-MSH的有效合成激动剂。我们的假设是 合成的α-MSH激动剂通过以下途径增强人体皮肤的光保护和预防皮肤癌 概述了α-MSH对黑素生成的刺激作用，以及对存活和 减少HMC的DNA损伤。为了研究这一假说，我们提出了三个具体目标。这个 具体目标1和2的目标是设计和合成有效的、稳定的、长效的片段类似物。 并测试他们通过选择性结合和检测a-MSH对HMC的所有影响的能力 在特定的目标3中，目标是测试最有效的激动剂对 含有正常HMC的培养皮肤替代品，以及来自皮肤高危人群的hMC 癌症(MC1R或p16INK4A基因突变携带者)，并评估可能的毒理学影响 以及这些激动剂的经皮渗透性。我们提出的皮肤癌预防方案的意义 策略在于利用a-MSH的有效合成片段类似物，这些片段类似物是选择性的超级激动剂 人类MC1R和增强皮肤的光保护，通过减少紫外线诱导的DNA损伤和 增加真黑素的合成。这一策略最终将特别降低皮肤癌的发病率。 在高危人群中，例如功能丧失的MC1R等位基因杂合子或表达 其他皮肤癌易感基因的突变，如黑色素瘤易感基因p16INK4A。

Skin cancer, in the form of melanoma, basal or squamous cell carcinoma, is the most commonformof cancer in the U.S.A. and is mainly caused by sun exposure, which results in DNA damage and photocarcinogenesis. There is mounting evidence for the significance of the melanocortin 1 receptor (MC1R) that is expressed on human melanocytes (hMC) and its endogenous ligands a-melanocyte stimulating hormone (a-melanocortin; a-MSH) and adrenocorticotropic hormone (ACTH) in photoprotection against skin cancer. First, activation of the MC1R by its ligands increases the synthesis of the photoprotective eumelanin, the black-brown form of melanin. Second, loss-of-function mutations in the human MC1R gene are associated with red hair phenotype, poor tanning ability and increased risk for skin cancer. Certain mutations in the gene for proopiomelanocortin, the precursorfor melanocortins, also result in red hair phenotype. Third, we discovered a novel role for a-MSH as a survival factor that rescueshMC from ultraviolet radiation (UVR>induced apoptosis and reduces DNAdamage. These effects are absent in hMC expressing loss-of-function MC1R alleles, which exhibit a reduced DNA repair capacity. Based on this evidence, the main goal of this proposal is to develop a new skin cancer preventative strategy based on utilizing potent synthetic agonists of a-MSH that can be delivered topically. Our hypothesis states that synthetic a-MSH agonists augment photoprotection in human skin and prevent skin cancer by recapitulating the stimulatory effects of a-MSH on melanogenesis, as well as on the survival and reduction in DNA damage of hMC. To investigate this hypothesis, three specific aims are proposed. The goal of Specific Aims 1and 2 is to design and synthesize potent, stable, long acting fragment analogs of a- MSH and test their ability to recapitulate all the effects of a-MSH on hMC by selectively binding and activating the MC1 R. In Specific Aim 3, the goal is to test the effects of the most effective agonists on cultured skin substitutes containing normal hMC, as well as hMCfrom individuals with a high risk for skin cancer (carriers of mutations in the MC1R or p16INK4Agene), and evaluate the possible toxicological effects and percutaneous permeability of these agonists. The significance of our proposed skin cancer prevention strategy lies in utilizing potent synthetic fragmentanalogs of a-MSH that are selective super agonists for the human MC1R and augment the photoprotection of the skin by reducing UVR-induced DNA damage and increasing eumelanin synthesis. This strategy will ultimately reduce the incidence of skin cancer particularly in high-risk population, such as individuals heterozygous for a loss-of-function MC1R allele or expressing mutations in other skin cancer susceptibility genes, such as the melanoma susceptibility gene p16INK4A.