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，是皮肤癌的最致命形式， 这是退伍军人中第五大诊断的癌症。退伍军人的黑色素瘤事件高于 平民，特别是在肤色浅，晒黑能力差的人中。超过65％的退伍军人有 这个表型。在伊拉克和阿富汗等地理区域部署数百万士兵 由于不可避免的每日过量的阳光暴露而没有最佳保护，因此增加了黑色素瘤的风险。 鉴于黑色素瘤的先进治疗选择的局限性，重要的是要专注于开发新的 减少事件的化学预防策略。我们的目标是制定预防黑色素瘤策略 基于靶向黑色皮质素1受体（MC1R），这是真正的黑色素瘤易感性的产物 基因已知是人类色素沉着的主要调节剂和黑素细胞对太阳紫外线的反应。我们 是第一个报告第二个发现MC1R的激活，这是膜结合的GS蛋白偶联的激活 受体在黑素细胞上通过其激动剂α-核细胞刺激马酮（α-甲状腺皮质素；α-MSH）表达的受体 通过增强DNA修复和抗氧化能力来减少紫外线诱导的DNA损伤 刺激光保护eumelanin的合成。其他人表明，表达的表达 MC1R的功能变异与紫外线签名突变和常见的体细胞相关 V600E突变在BRAF中，驱动黑色素作用。大约50％的白色高加索人，包括大约7个 百万退伍军人是MC1R变体的杂合载体，一种与增加风险有关的基因型 黑色素瘤。这些人将特别受益于我们的预防策略，这将增强 MC1R的激活。我们已经开发了α-MSH的四肽和三肽类似物，以模仿 α-MSH对人黑色素细胞，稳定且亲脂性，并且在其高选择性方面对 MC1R。这些肽的化妆品使用被已发表的专利应用所涵盖。四肽是 在激活MC1R信号方面，tripepptiDES的潜力高100倍，而tripepptides仅比α-MSH降低10倍 以及它在培养的人类黑素细胞中的下游影响。这些肽增强了紫外线诱导的修复 DNA光产物，以及没有任何UV的人类皮肤替代品（CSS）的色素沉着增加 接触。这些小肽与α-MSH不同，不应引起免疫抑制，因为它们缺乏 α-MSH的COOH末端11-13氨基酸残差（Lys-Pro-Val）负责其抗 炎症和免疫抑制作用。我们提出α-MSH的三肽和四肽类似物 对MC1R的选择性将作为局部用剂开发，以刺激皮肤色素沉着并减少 紫外线诱导的DNA损伤，以维持黑色素细胞的基因组稳定性，因此减少了 退伍军人黑色素瘤的风险。我们的具体目的是：i：开发MC1R选择性的局部公式 四肽和三肽肽，通过表皮表现出它们的渗透，对其进行量化 皮肤层中的浓度，并在体外验证其对完整人皮肤或CSS的光保护作用 局部应用。 ii。测试两个辣椒对临床前动物模型的影响，包括 将移植到免疫缺陷小鼠的人类CSS，以及具有类似皮肤的微型猪模型 人类。终点将包括测量DNA损伤，色素沉着的变化，增殖和 角质形成细胞和黑素细胞的凋亡。将获得初步药代动力学的血液样本 将检查测试和组织样品的总毒理学作用。这个项目的结果应该 促使我们更加接近研究新药和进行临床试验的申请。