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: 8958319
• 负责人: ZALFA ABDEL-MALEK
• 金额: $ 22.16万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958319
• 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; Human; Hyperplasia; Incidence; Individual; Investigation; Life; Melanins; Melanocortin 1 Receptor; Melanocyte stimulating hormone; 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; public health relevance; 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（由申请人提供）：本修订申请将检验以下假设：α-黑皮质素（α-MSH）的小肽类似物是黑皮质素1受体（MC 1 R）的选择性激动剂，可通过增强紫外线（UV）诱导的DNA损伤修复和刺激黑素生成来预防转基因小鼠黑色素瘤模型中的黑色素瘤形成。我们开创了对MC 1 R及其激动剂α-黑素细胞刺激素（α-MSH）的研究，发现它们通过激活DNA修复和抗氧化途径来减轻UV诱导的DNA损伤程度。这些发现阐明了MC 1 R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MC 1 R等位基因变体的表达会增加黑色素瘤风险。我们对MC 1 R/α-MSH轴的研究使我们开始开发一种基于高选择性α-MSH小类似物靶向MC 1 R的黑色素瘤化学预防策略。我们已经设计并测试了大量的小α-MSH类似物，三肽和四肽，它们是MC 1 R的完全激动剂，并模拟生理α-MSH对人黑素细胞的所有作用。在本项目中，我们建议检测一种三肽LK 514和一种四肽LK 467，这两种肽是根据其对人黑素细胞的效力选择的，重要的是，它们对MC 1 R的独特选择性、稳定性和亲脂性。在基于细胞和组织的测定中，两种肽都没有任何细胞毒性作用。我们将在两种与人黑色素瘤相关的小鼠模型中测试这些类似物预防黑色素瘤发生的功效，i）K14- SCF; Mc 1 r e/+转基因小鼠，Mc 1 r中隐性黄色突变的杂合子，一种红头发MC 1 R变体杂合子的人模型，其代表美国和北方大部分白色人群，并且由于以下原因而具有增加的黑素瘤风险：降低的MC 1 R活性，和; ii）HGF转基因小鼠，UV诱导的黑素瘤模型。我们将研究这些类似物的能力，以减少紫外线诱导的DNA损伤的程度，刺激真黑素合成，并抑制黑素细胞增生，黑色素瘤的形成，进展和多样性。这些体内实验对于将这些类似物推向I期临床试验至关重要。在转移性黑色素瘤无法治愈的情况下，由于迫切需要有效的黑色素瘤预防策略，该应用是重要的，该策略将降低与该疾病相关的死亡率和发病率，并阻止其发病率的持续增加。我们提出的策略是创新的，因为我们的类似物具有对MC 1 R具有高度选择性的独特特征，这减少了由于与其他MC受体结合而引起的脱靶效应，此外，它们的小尺寸，稳定性和亲脂性应该允许局部递送和持久的效果。这一策略将使数百万皮肤白皙、晒黑能力差的高危人群受益，包括MC 1 R变异杂合子或其他黑色素瘤易感基因（如p16）突变的人群。