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

• 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
• 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

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最具侵袭性的癌症之一。它在体内转移的能力 再加上对传统抗癌化疗的耐药性，使黑色素瘤极难 解药。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著事件之一是C-MYC蛋白的数量增加。丙- MYC是一个转录因子。大量的C-MYC与多种类型的人类 癌症主要发生在更晚期、侵袭性更强的阶段。相应地，C-MYC已经被证明 对包括黑色素瘤在内的多种小鼠实验性肿瘤的生长至关重要。尽管如此，尽管 对C-MYC在肿瘤发展中的核心作用的广泛认识，只有一种靶向C-MYC的药物是 目前正在进行临床试验。 我们建议的主要目标是开发抗C-MYC药物，能够消除 黑色素瘤可以单独使用，也可以与现有的抗癌药物联合使用。为此，通过应用不同的 通过实验分析，我们已经筛选出一组34,000种单独的化学物质，用于那些能够消除 癌细胞中的c-myc或其功能的抑制。我们能够识别出一种先导化合物AM7， 减少小鼠的肿瘤生长，没有明显的副作用，如痛苦或体重减轻。 从机制上讲，我们已经确定AM7不降低C-MYC的mRNA或蛋白水平，但抑制 C-MYC与SWI/SNF复合物相互作用的能力。 在目前的应用中，我们提出了一项旨在确定AM7分子机制的研究计划 AM7的活性和作为一种新的黑色素瘤治疗策略的应用。