The novel PRMT5-substrate adaptor interface provides a therapeutic target in MTAP null tumors

新型PRMT5-底物适配器接口为MTAP无效肿瘤提供了治疗靶点

• 批准号: 10458821
• 负责人: Kathleen Mulvaney
• 金额: $ 3.37万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458821
• 关键词: Adaptor Signaling Protein; Address; Arginine; Binding; Binding Proteins; Binding Sites; Biological Assay; CDKN2A gene; Catalytic Domain; Cell physiology; Cells; Chromatin; Chromosome 9; Complex; Dependence; Disease; Enzymes; Face; Genes; Genetic Transcription; Glioblastoma; Growth; In Vitro; Length; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammalian Cell; Measures; Messenger RNA; Methylation; Methyltransferase; Mutation; Pancreatic Ductal Adenocarcinoma; Patients; Peptides; Proteins; Proteomics; RNA Splicing; Research Proposals; Role; Site; Specificity; Spliceosomes; Techniques; Therapeutic; Tumor Suppressor Genes; Work; arginine methyltransferase; base; cancer type; effective therapy; experimental study; in vivo; inhibitor/antagonist; knock-down; mutant; novel; pancreatic cancer model; recruit; scaffold; therapeutic target; tumor; tumor growth

Project Abstract Pancreatic cancer is one of the most lethal types of cancer worldwide. Less than 7% of patients survive this deadly disease. Despite efforts, few effective therapies exist. Intriguingly, the methyltransferase PRMT5 has been identified as a cancer dependency in MTAP null tumors, which constitute 15% of all tumors and 30% of pancreatic ductal adenocarcinomas. Therefore, PRMT5 is an attractive target in pancreatic cancer. This PRMT5 dependency arises due to the passenger deletion of the MTAP gene that is adjacent to the frequently deleted tumor suppressor gene CDKN2A on chromosome 9. In tumors lacking MTAP, its substrate, methylthioadenosine (MTA) accumulates and competitively inhibits the PRMT5 enzyme. While therapeutic targeting of PRMT5 has focused on targeting the catalytic pocket, our preliminary studies demonstrate a novel and potentially important face of the PRMT5 methylosome that may overcome cellular specificity and efficacy issues with PRMT5 catalytic inhibitors. Therefore, I hypothesize that the newly identified PRMT5-substrate adaptor interface is required for PRMT5 activity and is thus essential for the growth of MTAP null tumors. Through the following two Aims, we will address whether the PRMT5-substrate adaptor site is required for all or particular PRMT5 functions and establish whether disruption of this protein interaction site might have a therapeutic benefit in pancreatic cancer.

项目摘要 胰腺癌是全球最致命的癌症之一。不到7％的患者生存 这种致命的疾病。尽管做出了努力，但几乎没有有效的疗法。有趣的是，甲基转移酶PRMT5具有 被确定为MTAP无效肿瘤的癌症依赖性，占所有肿瘤的15％，30％ 胰腺导管腺癌。因此，PRMT5是胰腺癌的吸引力。这个prmt5 依赖性是由于MTAP基因的乘客删除而引起的，该基因与经常删除 染色体9上的肿瘤抑制基因CDKN2A。 （MTA）积累并竞争抑制PRMT5酶。 PRMT5的治疗靶向 我们的初步研究专注于靶向催化口袋，证明了一种新颖且潜在的重要性 PRMT5甲基体的面部可能会克服PRMT5催化的细胞特异性和功效问题 抑制剂。因此，我假设新近识别的prmt5-Substrate适配器接口需要 PRMT5活性，因此对于MTAP无效肿瘤的生长至关重要。通过以下两个目标，我们 将解决所有或特定PRMT5功能需要的PRMT5-SUBSTRATE适配器网站以及 确定该蛋白质相互作用部位的破坏是否可能对胰腺癌具有治疗益处。