Inhibition of MYC interactions with chromatin-remodeling factors as a novel anti-melanoma strategy

抑制 MYC 与染色质重塑因子的相互作用作为一种新型抗黑色素瘤策略

基本信息

批准号：
9808913
负责人：
Mikhail Nikiforov
金额：
$ 12.61万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808913
关键词：
Adverse effects Antineoplastic Agents Apoptosis BRAF gene Biological Assay Body Weight decreased C-terminal Cancerous Cells Chemicals Chromatin Chromatin Remodeling Factor Clinical Trials Complex DNA Polymerase II Data Databases Dependence Development Distress Drug Targeting Event Experimental Neoplasms Family Family member Foundations Gene Targeting Genes Genetic Genetic Suppression Genetic Transcription Goals Growth Human Immunocompromised Host Individual International Lead MYC Family Protein Maintenance Malignant Neoplasms Mediating Melanoma Cell Messenger RNA Metabolism Metastatic Melanoma Molecular Mus Mutation Neoplasm Metastasis Normal tissue morphology Oncoproteins Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Phosphorylation Process Proteins Proto-Oncogene Proteins c-myc RNA Research Resistance Role Russia SWI/SNF Family Complex Specimen Survival Rate System Testing The Cancer Genome Atlas Transcriptional Activation Xenograft procedure anti-cancer base c-myc Genes cancer survival chemotherapy improved inhibitor/antagonist melanoma member metabolome mouse model novel overexpression promoter recruit response screening senescence small hairpin RNA small molecule therapeutic target transcription factor transcriptome treatment strategy tumor tumor growth

项目摘要

Malignant melanoma is one of the most aggressive types of human cancers. Its ability to metastasize in combination with resistance to conventional anticancer chemotherapy makes melanoma extremely difficult to cure. As a consequence, the median survival of patients with metastatic melanoma is merely 8.5 months. One of the prominent events in metastatic melanomas is increase in the amounts of the protein C-MYC. C- MYC is a transcription factor. High amounts of C-MYC have been associated with multiple types of human cancers predominantly at more advanced, aggressive stages. Accordingly, C-MYC has been demonstrated essential for growth of many types of experimental tumors in mice including melanoma. None the less, despite wide recognition of the central role of C-MYC in tumor development, only a single drug targeting C-MYC is currently being tested in clinical trials. The major goal of our proposal is to develop anti-C-MYC pharmaceutical agents capable of elimination of melanoma either alone or in combination with existent anti-cancer drugs. To this end, by applying different experimental assays, we have screened a set of 34,000 individual chemicals for those capable of elimination of C-MYC in cancerous cells or inhibition of its function. We were able to identify a lead compound, AM7, that decreases tumor growth in mice without noticeable side effects such as distress or weight loss. Mechanistically, we have identified that AM7 does not decrease C-MYC mRNA or protein levels but inhibits the ability of C-MYC to interact with SWI/SNF complexes. In the present application, we propose a research plan aiming at identifying molecular mechanisms of AM7 activity and establishing the use of AM7 as a novel melanoma treatment strategy.

恶性黑色素瘤是人类癌症中最具侵略性的类型之一。它转移的能力结合对常规抗癌化疗的耐药性使黑色素瘤极难治愈。结果，转移性黑色素瘤患者的中位存活仅为8.5个月。转移性黑色素瘤中突出的事件之一是蛋白质C-MYC的量增加。 c- MYC是转录因子。大量C-MYC与多种类型的人有关癌症主要是在更高级，更具侵略性的阶段。因此，已经证明了C-MYC 包括黑色素瘤在内的小鼠中多种类型的实验肿瘤的生长至关重要。尽管如此，尽管广泛认识C-MYC在肿瘤发育中的核心作用，只有单一的靶向C-Myc是目前正在临床试验中进行测试。我们建议的主要目标是开发能够消除能够消除的抗C-MYC药物黑色素瘤单独或与现有的抗癌药物结合使用。为此，应用不同的实验测定，我们已经筛选了一组34,000个单独的化学物质，以消除能够消除的化学物质 C-Myc在癌细胞中或抑制其功能。我们能够识别出铅化合物AM7，降低小鼠的肿瘤生长，而没有明显的副作用，例如遇险或体重减轻。从机械上讲，我们已经确定AM7不会降低C-MYC mRNA或蛋白质水平，而是抑制 C-MYC与SWI/SNF复合物相互作用的能力。在本应用中，我们提出了一个研究计划，旨在识别AM7的分子机制活动并确定将AM7用作新型黑色素瘤治疗策略。