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：
9380591
负责人：
Mikhail Nikiforov
金额：
$ 13.93万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
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/9380591
关键词：
Adverse effects Alpha Cell 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 Dependency 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 Recruitment Activity Research Resistance Role Russia SWI/SNF Family Complex Specimen Survival Rate System Testing The Cancer Genome Atlas Transcriptional Activation Xenograft procedure base c-myc Genes cancer survival chemotherapy improved inhibitor/antagonist melanoma member metabolome mouse model novel overexpression promoter 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.

恶性黑色素瘤是最具侵袭性的人类癌症类型之一。其转移能力与传统抗癌化疗的耐药性相结合使得黑色素瘤极难治愈治愈。因此，转移性黑色素瘤患者的中位生存期仅为 8.5 个月。转移性黑色素瘤的显着事件之一是蛋白质 C-MYC 数量的增加。 C- MYC 是一种转录因子。大量的 C-MYC 与多种人类类型有关癌症主要处于晚期、侵袭性阶段。因此，C-MYC已被证明对于小鼠中多种类型的实验性肿瘤（包括黑色素瘤）的生长至关重要。尽管如此，尽管人们广泛认识到 C-MYC 在肿瘤发展中的核心作用，目前只有一种针对 C-MYC 的药物目前正在临床试验中进行测试。我们提案的主要目标是开发能够消除的抗 C-MYC 药剂单独或与现有抗癌药物联合治疗黑色素瘤。为此，通过应用不同通过实验分析，我们筛选了一组 34,000 种单独的化学物质，以寻找能够消除 C-MYC在癌细胞中或抑制其功能。我们能够鉴定出一种先导化合物 AM7，减少小鼠肿瘤的生长，而没有明显的副作用，例如痛苦或体重减轻。从机制上讲，我们已经确定 AM7 不会降低 C-MYC mRNA 或蛋白质水平，但会抑制 C-MYC 与 SWI/SNF 复合物相互作用的能力。在本申请中，我们提出了一项旨在确定AM7分子机制的研究计划活性并建立 AM7 作为新型黑色素瘤治疗策略的用途。