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: 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
• 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

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。它的转移能力 结合对常规抗癌化疗的抗性使得黑色素瘤极难 疗方因此，转移性黑素瘤患者的中位生存期仅为8.5个月。 转移性黑色素瘤中的突出事件之一是蛋白质C-MYC的量增加。C-型 MYC是一种转录因子。大量的C-MYC与多种类型的人类肿瘤相关。 癌症主要发生在更晚期的侵袭性阶段。因此，C-MYC已被证明 对于小鼠中许多类型的实验性肿瘤（包括黑素瘤）的生长是必需的。尽管如此， C-MYC在肿瘤发展中的核心作用得到广泛认可，目前只有一种靶向C-MYC的药物， 目前正在进行临床试验。 我们建议的主要目标是开发能够消除C-MYC的抗C-MYC药剂。 黑色素瘤，单独或与现有抗癌药物组合。为此，通过采用不同的 在实验测定中，我们筛选了一组34，000种单独的化学品，以确定哪些化学品能够消除 C-MYC在癌细胞中或抑制其功能。我们鉴定出了一种先导化合物AM 7 减少小鼠的肿瘤生长，而没有明显的副作用，如痛苦或体重减轻。 从机制上讲，我们已经确定AM 7不降低C-MYC mRNA或蛋白水平，但抑制C-MYC mRNA或蛋白水平。 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AM 7分子机制的研究计划 活性，并建立AM 7作为一种新的黑色素瘤治疗策略的用途。