Melanoma prevention by MC1R selective small peptide analogs of alpha MSH

通过 MC1R 选择性 α MSH 小肽类似物预防黑色素瘤

• 批准号: 9105353
• 负责人: ZALFA ABDEL-MALEK
• 金额: $ 18.47万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-03 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105353
• 关键词: Acute; Agonist; Alleles; Antioxidants; Binding; Biological Assay; Cell surface; Cells; Chemoprevention; Cyclic AMP; DNA Damage; DNA Repair; DNA photoproducts; Deoxyguanosine; Disease; Dose; Epidemiologic Studies; Epidermis; Gene Expression; Generations; Genes; Goals; Hair; Hair Color; Health; Human; Hyperplasia; Incidence; Individual; Investigation; Life; Melanins; Melanocortin 1 Receptor; Melanogenesis; Metastatic Melanoma; Modeling; Molecular Weight; Monophenol Monooxygenase; Morbidity - disease rate; Mus; Mutation; Neonatal; Northern Europe; Nucleotide Excision Repair; Oxidative Stress; Pathway interactions; Peptides; Phase I Clinical Trials; Phenotype; Physiological; Pigmentation physiologic function; Population; Prevention; Prevention strategy; Proteins; Pyrimidine Dimers; Radiation Induced DNA Damage; Reactive Oxygen Species; Reporting; Research; Risk; Role; Skin; Skin Cancer; Skin tanning; Susceptibility Gene; Testing; Time; Tissues; Topical application; Transgenic Mice; Ultraviolet Rays; Variant; alpha-Melanocyte stimulating hormone; analog; base; brief intervention; cytotoxic; cytotoxicity; design; efficacy testing; eumelanin; genetic variant; high risk; hormone analog; in vivo; innovation; lipophilicity; loss of function; melanocyte; melanoma; mortality; mouse model; oxidative DNA damage; peptide analog; preclinical study; prevent; radiation response; receptor; receptor coupling; receptor function; repaired; research study; response; sensor; tumor

 DESCRIPTION (provided by applicant): This revised application will test the hypothesis that small peptide analogs of α-melanocortin (α-MSH) that are selective agonists of the melanocortin 1 receptor (MC1R) will prevent melanoma tumor formation in transgenic mouse melanoma models by enhancing repair of ultraviolet radiation (UV)-induced DNA damage and stimulating melanogenesis. We have pioneered the research on the MC1R and its agonist α-melanocyte stimulating hormone (α-MSH), and discovered their role in reducing the extent of UV-induced DNA damage by activating DNA repair and antioxidant pathways. These findings illuminated how the MC1R functions as a melanoma predisposition gene, and why expression of loss-of-function MC1R allelic variants that are strongly associated with red hair phenotype increases melanoma risk. Our research on MC1R/α-MSH axis led us to begin developing a melanoma chemoprevention strategy based on targeting the MC1R by highly selective small analogs of α-MSH. We have designed and tested a large panel of small α-MSH analogs, tri- and tetrapeptides that are full agonists of the MC1R and mimic the physiological α-MSH in all its effects on human melanocytes. In this project, we are proposing to test one tripeptide, LK 514, and one tetrapeptide, LK 467, that were selected based on their potency on human melanocytes, and importantly, for their unique selectivity for the MC1R, stability, and lipophilicity. Neither peptide had any cytotoxic effects in cell- and tissue-based assays. We will test the efficacy of these analogs to prevent melanomagenesis in two mouse models that are relevant to human melanoma, i) K14- SCF;Mc1r e/+ transgenic mice, heterozygous for the recessive yellow mutation in Mc1r, a model for humans heterozygous for a red hair MC1R variant who represent a large sector of the white population in the U.S.A. and Northern Europe and have increased risk for melanoma due to reduced MC1R activity, and; ii) HGF transgenic mice, a model for UV-inducible melanoma. We will investigate the ability of these analogs to reduce the extent of UV-induced DNA damage, stimulate eumelanin synthesis, and inhibit melanocytic hyperplasia, melanoma formation, progression and multiplicity. These in vivo experiments are crucial in order to advance these analogs towards a Phase I Clinical Trial. In the absence of a cure for metastatic melanoma, this application is significant due to the critical need for effective melanoma prevention strategies that will reduce the mortality and morbidity associated with the disease, and halt the continuous increase in its incidence. Our proposed strategy is innovative, since our analogs have the unique feature of being highly selective to MC1R, which reduces off-target effects due to binding to other MC receptors, in addition to their small size, stability and lipophilicity that should allow for topical delivery and long lasting effcts. This strategy should benefit millions of high risk individuals with fair skin and poor tanning ability, including those heterozygous for MC1R variant, or harboring mutations in other melanoma predisposition genes, such as p16.

 描述(申请人提供)：这项修订后的申请将测试这样一个假设，即α-黑素皮质素的小肽类似物(α-MSH)是黑素皮质素1受体(MC1R)的选择性激动剂，通过促进紫外线辐射(UV)诱导的DNA损伤的修复和刺激黑素生成，可以防止转基因小鼠黑色素瘤模型中黑色素瘤的形成。我们率先对MC1R及其激动剂α黑素细胞刺激素(α-MSH)进行了研究，并发现它们通过激活DNA修复和抗氧化途径在减少紫外线诱导的DNA损伤程度中的作用。这些发现阐明了MC1R如何作为黑色素瘤易感基因发挥作用，以及为什么与红发表型密切相关的功能丧失的MC1R等位基因变异的表达增加了黑色素瘤的风险。我们对MC1R/α-MSH轴的研究引导我们开始开发一种基于高度选择性的α-MSH类似物靶向MC1R的黑色素瘤化学预防策略。我们设计并测试了一大批小的α-MSH类似物，三肽和四肽，它们是MC1R的完全激动剂，并在所有对人类黑素细胞的作用上模拟了生理性的α-MSH。在这个项目中，我们建议测试一个三肽LK 514和一个四肽LK 467，它们是根据它们对人黑素细胞的效力而选择的，重要的是，它们对MC1R的独特选择性、稳定性和亲脂性。在基于细胞和组织的分析中，这两种多肽都没有任何细胞毒性作用。我们将在两个与人类黑色素瘤相关的小鼠模型上测试这些类似物在预防黑色素瘤发生方面的有效性：i)K14-SCF；MC1R e/+转基因小鼠，MC1R隐性黄色突变的杂合子；人类的一个模型，红发MC1R变体的杂合子代表美国和北欧的很大一部分白人人口，由于MC1R活性降低而增加患黑色素瘤的风险；ii)HGF转基因小鼠，一种紫外线诱导的黑色素瘤模型。我们将研究这些类似物减少紫外线诱导的DNA损伤的程度，刺激真黑素合成，抑制黑素细胞增殖，黑色素瘤的形成，进展和多样性的能力。这些体内实验对于推动这些类似物进入I期临床试验至关重要。在没有治愈转移性黑色素瘤的情况下，这种应用意义重大，因为迫切需要有效的黑色素瘤预防策略，以减少与疾病相关的死亡率和发病率，并阻止其发病率的持续增加。我们建议的策略是创新的，因为我们的类似物具有对MC1R高度选择性的独特特征，除了它们的小尺寸、稳定性和亲脂性之外，它还减少了由于与其他MC受体结合而产生的非靶点效应，这应该允许局部给药和持久的效果。这一策略将使数百万皮肤白皙、晒黑能力较差的高危个体受益，包括那些MC1R变异杂合子或其他黑色素瘤易感基因突变的人，如p16。