Targeting the Melanocortin 1 Receptor by Selective Small Analogs of α-Melanocortin for Melanoma Prevention

通过选择性α-黑皮质素小类似物靶向黑皮质素 1 受体预防黑色素瘤

• 批准号: 10474302
• 负责人: ZALFA ABDEL-MALEK
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474302
• 关键词: Afghanistan; Age; Age-Years; Agonist; Amino Acids; Animal Model; Antiinflammatory Effect; Antioxidants; Apoptosis; Autopsy; BRAF gene; Biological Assay; Biological Availability; Blood Tests; Blood specimen; CDKN2A gene; Caucasians; Cells; Chemoprevention; Chemopreventive Agent; Climate; Conduct Clinical Trials; Cosmetics; Country; Coupled; Cutaneous; Cutaneous Melanoma; DNA Damage; DNA Repair; DNA photoproducts; Data; Development; Diffusion; Disease; Drug Kinetics; Epidermis; Etiology; Experimental Models; Exposure to; Family suidae; Formulation; General Population; Genome Stability; Genotype; Geographic Locations; Goals; Hair; Hormones; Human; Immunodeficient Mouse; Immunosuppression; In Vitro; Incidence; Individual; Investigational New Drug Application; Iraq; Legal patent; Light; Measurement; Melanocortin 1 Receptor; Membrane; Methods; Military Personnel; Morbidity - disease rate; Mutation; Not Hispanic or Latino; Nude Mice; Outcome; Peptides; Phenotype; Physiological; Pigmentation physiologic function; Pigments; Prevention; Prevention strategy; Property; Proteins; Publishing; Receptor Gene; Receptor Signaling; Reporting; Risk; Seminal; Skin; Skin Cancer; Skin Pigmentation; Skin Substitutes; Skin tanning; Soldier; Sun Exposure; Susceptibility Gene; System; Testing; The Sun; Therapeutic; Tissue Sample; Topical agent; Topical application; Toxicology; UV Radiation Exposure; UV induced; UV induced DNA damage; Ultraviolet Rays; Variant; Veterans; age group; alpha-Melanocyte stimulating hormone; analog; base; cancer diagnosis; cancer risk; eumelanin; genetic variant; high risk; high risk population; hormone analog; hot climate; in vivo Model; keratinocyte; lipophilicity; loss of function; lysylproline; melanocyte; melanoma; melanomagenesis; military men; military veteran; mortality; mutation carrier; novel; novel chemoprevention; peptide analog; peptidomimetics; photoprotection; porcine model; pre-clinical; prevent; receptor; repaired; response; skin color; solar ultraviolet radiation

Solar ultraviolet radiation (UV) is the main etiological factor for melanoma, the deadliest form of skin cancer, and the fifth most diagnosed cancer in veterans. The incidence of melanoma is higher in veterans than in civilians, particularly in individuals with light skin color and poor tanning ability. Over 65% of all veterans have this phenotype. Deployment of millions of soldiers in geographical areas such as Iraq and Afghanistan increases their risk for melanoma due to unavoidable daily excessive sun exposure without optimal protection. Given the limitations of advanced therapeutic options for melanoma, it is important to focus on developing new chemoprevention strategies to reduce its incidence. Our goal is to develop a melanoma prevention strategy based on targeting the melanocortin 1 receptor (MC1R), the product of a bona fide melanoma predisposition gene known to be a major regulator of human pigmentation and the response of melanocytes to solar UV. We were the first to report the seminal findings that activation of the MC1R, a membrane-bound Gs protein-coupled receptor expressed on melanocytes, by its agonist α-melanocyte stimulating hormone (α-melanocortin; α-MSH) reduces UV-induced DNA damage by enhancing DNA repair and antioxidant capacities, in addition to stimulating the synthesis of photoprotective eumelanin. Others have shown that expression of a loss-of- function variant of MC1R is associated with increased UV signature mutations and the common somatic V600E mutation in BRAF, that drive melanomagenesis. About 50% of all White Caucasians, including about 7 million veterans, are heterozygous carriers of a MC1R variant, a genotype associated with increased risk for melanoma. These individuals will particularly benefit from our prevention strategy that will enhance the activation of the MC1R. We have developed tetra- and tripeptide analogs of α-MSH that mimic the effects of α-MSH on human melanocytes, and are stable and lipophilic, and unique in their high selectivity for the MC1R. The cosmetic use of these peptides is covered by a published patent application. The tetrapeptides are 100 fold more potent, and the tripeptides are only 10 fold less potent than α-MSH in activating MC1R signaling and its downstream effects in cultured human melanocytes. These peptides enhanced repair of UV-induced DNA photoproducts, and increased pigmentation of cultured human skin substitutes (CSS) without any UV exposure. These small peptides, unlike α-MSH, should not cause immunosuppression, since they lack the COOH-terminal 11-13 amino acid residues (Lys-Pro-Val) of α-MSH that are responsible for its anti- inflammatory and immunosuppressive effects. We propose that our tri- and tetrapeptide analogs of α-MSH that are selective for the MC1R will be developed as topical agents to stimulate skin pigmentation and reduce UV-induced DNA damage, in order to maintain the genomic stability of melanocytes, and therefore reduce the risk for melanoma in veterans. Our Specific Aims are: I: To develop topical formulations of MC1R-selective tetrapeptide and tripeptidepeptide, demonstrate their permeation through the epidermis, quantify their concentrations in the skin layers, and validate their photoprotective effects on intact human skin or CSS in vitro when applied topically. II. To test the effects of the two peptides on pre-clinical animal models, including human CSS that will be grafted onto immunodeficient mice, and a miniature pig model with skin similar to that of humans. Endpoints will include measurement of DNA damage, changes in pigmentation, proliferation and apoptosis of keratinocytes and melanocytes. Blood samples will be obtained for preliminary pharmacokinetics testing and tissue samples will be examined for gross toxicological effects. The outcome of this project should advance us closer towards application for Investigational New Drug and conducting clinical trials.

太阳紫外线辐射（UV）是黑色素瘤的主要病因，黑色素瘤是最致命的皮肤癌， 退伍军人中诊断出的第五大癌症 退伍军人中黑色素瘤的发病率高于普通人。 平民，特别是浅肤色和晒黑能力差的人，超过 65% 的退伍军人都有这种情况。 在伊拉克和阿富汗等地区部署了数百万士兵。 由于每天不可避免地过度暴露在阳光下而没有最佳的保护，因此增加了患黑色素瘤的风险。 鉴于黑色素瘤先进治疗方案的局限性，重点开发新的治疗方案非常重要 减少其发病率的化学预防策略我们的目标是制定黑色素瘤预防策略。 基于针对黑皮质素 1 受体 (MC1R)，这是真正的黑色素瘤易感性的产物 已知该基因是人类色素沉着和黑素细胞对太阳紫外线反应的主要调节因子。 是第一个报告这一开创性发现的人，即 MC1R 的激活，一种膜结合的 Gs 蛋白偶联 黑素细胞上表达的受体，通过其激动剂 α-黑素细胞刺激激素（α-黑皮质素；α-MSH） 通过增强 DNA 修复和抗氧化能力来减少紫外线引起的 DNA 损伤，此外 其他人已经证明了光保护性真黑色素的表达的丧失。 MC1R 的功能变异与增加的 UV 特征突变和常见的体细胞突变有关。 BRAF 中的 V600E 突变会导致约 50% 的白种人发生黑色素瘤，其中包括约 7 例。 百万退伍军人是 MC1R 变体的杂合携带者，该基因型与增加的风险相关 这些人将特别受益于我们的预防策略，该策略将增强黑色素瘤的发生。 我们开发了 α-MSH 的四肽和三肽类似物，可以模拟 MC1R 的作用。 α-MSH 对人类黑色素细胞具有稳定和亲脂性，其独特之处在于对黑色素细胞的高选择性 已发表的专利申请涵盖了这些肽的化妆品用途。 在激活 MC1R 信号传导方面，三肽的效力比 α-MSH 强 100 倍，但效力仅低 10 倍 及其对培养的人黑素细胞的下游影响。这些肽增强了紫外线诱导的修复。 DNA 光产品，以及在没有任何紫外线的情况下增加培养人类皮肤替代品 (CSS) 的色素沉着 与 α-MSH 不同，这些小肽不会引起免疫抑制，因为它们缺乏。 α-MSH 的 COOH 末端 11-13 个氨基酸残基 (Lys-Pro-Val) 负责其抗- 我们提出我们的 α-MSH 的三肽和四肽类似物。 对 MC1R 具有选择性的药物将被开发为局部制剂，以刺激皮肤色素沉着并减少 紫外线引起的DNA损伤，以维持黑素细胞基因组的稳定性，从而减少 我们的具体目标是： I：开发 MC1R 选择性局部制剂。 四肽和三肽，证明它们通过表皮的渗透性，量化它们的 皮肤层中的浓度，并在体外验证其对完整人体皮肤或 CSS 的光保护作用 II. 测试两种肽对临床前动物模型的影响。 将被移植到免疫缺陷小鼠身上的人类CSS，以及皮肤与之相似的小型猪模型 人类的终点将包括测量 DNA 损伤、色素沉着、增殖和 获取角质形成细胞和黑素细胞的凋亡用于初步药代动力学。 将检查测试和组织样本的总体毒理学效应。 使我们更接近研究性新药的申请和进行临床试验。