Discovery of Alpha-MSH Analogs for Skin Cancer Prevention

发现用于预防皮肤癌的 Alpha-MSH 类似物

• 批准号: 7198365
• 负责人: ZALFA ABDEL-MALEK
• 金额: $ 32.4万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198365
• 关键词: DNA damage; analog; cancer prevention; clinical research; gene mutation; genes; human; melanocyte; melanoma; photoprotection; skin; skin neoplasms

DESCRIPTION (provided by applicant): Skin cancer, in the form of melanoma, basal or squamous cell carcinoma, is the most common form of 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 precursor for melanocortins, also result in red hair phenotype. Third, we discovered a novel role for a-MSH as a survival factor that rescues hMC from ultraviolet radiation (UVR>induced apoptosis and reduces DNA damage. 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 1 and 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 hMC from 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 fragment analogs 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.

描述(申请人提供)：皮肤癌，以黑色素瘤、基底细胞癌或鳞状细胞癌的形式出现，是美国最常见的癌症形式，主要由阳光照射引起，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(MC1R)表达于人黑素细胞(HMC)及其内源性配体α-黑素细胞刺激素(a-Melocortin；a-MSH)和促肾上腺皮质激素(ACTH)，在皮肤癌的光保护中具有重要意义。首先，MC1R被其配体激活会增加光保护真黑素的合成，真黑素是黑色素的一种黑褐色形式。其次，人类MC1R基因功能缺失突变与红发表型、晒黑能力差和皮肤癌风险增加有关。黑素皮质素前体--前阿片黑素皮质素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，它可以从紫外线(UVR&GT；)诱导的细胞凋亡中拯救HMC，并减少DNA损伤。这些影响在表达功能丧失的MC1R等位基因的HMC中不存在，这种等位基因表现出DNA修复能力降低。基于这一证据，这项建议的主要目标是开发一种新的皮肤癌预防策略，该策略基于利用可以局部给药的a-MSH的有效合成激动剂。我们的假设表明，合成的a-MSH激动剂通过概括a-MSH对黑素生成的刺激作用，以及对HMC存活和减少DNA损伤的作用，增强了对人类皮肤的光保护，并预防皮肤癌。为了研究这一假说，我们提出了三个具体目标。特定目标1和2的目标是设计和合成有效、稳定、长效的a-MSH片段类似物，并测试它们通过选择性结合和激活MC1 R来概括a-MSH对HMC的所有作用的能力。在特定目标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癌高危人群(MC1R或p16INK4Agene突变携带者)的HMC的影响，并评估这些激动剂可能的毒理学效应和经皮渗透性。我们提出的皮肤癌预防策略的意义在于利用有效的合成片段类似物a-MSH是人类MC1R的选择性超级激动剂，并通过减少UVR诱导的DNA损伤和增加真黑素的合成来增强皮肤的光保护。这一策略将最终降低皮肤癌的发病率，特别是在高危人群中，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突变的个人，如黑色素瘤易感基因p16INK4A。