Mechanistic Dissection of an Arginine Methyltransferase Dependency in Cancer

癌症中精氨酸甲基转移酶依赖性的机制剖析

• 批准号: 9314681
• 负责人: Frederick H Wilson
• 金额: $ 17.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314681
• 关键词: Adenine; Adverse effects; Advisory Committees; Arginine; Award; BRAF gene; Biological; Biological Models; Biological Process; Biology; CDK4 gene; CDKN2A gene; Cancer cell line; Cell Survival; Cells; Cleaved cell; Clinical; Clinical Oncology; Collection; Cyclin-Dependent Kinases; Cytotoxic Chemotherapy; DNA; DNA Sequence Alteration; Dana-Farber Cancer Institute; Data Set; Dependency; Development; Dissection; Drug resistance; Enzymes; Epidermal Growth Factor Receptor; Event; Expression Library; Gene Expression; Genes; Genetic; Genetic Determinism; Genome; Genomic approach; Genomics; Glioblastoma; Goals; Human; Immunotherapy; Impairment; Individual; Institutes; Lead; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of pancreas; Medicine; Mentors; Mentorship; Messenger RNA; Methionine; Methodology; Methylation; Methyltransferase; Modality; Morbidity - disease rate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Pathway interactions; Positioning Attribute; Preclinical Testing; Predisposition; Prevalence; Proteins; Publishing; Purines; RNA Processing; RNA interference screen; RNA, Messenger, Splicing; Recruitment Activity; Recurrence; Refractory; Research; Research Personnel; Resources; Role; Side; Spliceosome Assembly Pathway; Spliceosomes; Therapeutic; Thioguanine; Thoracic Oncology; Time; Translating; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; actionable mutation; arginine methyltransferase; cancer cell; chromatin remodeling; clinical practice; collaborative approach; experience; functional genomics; genome-wide; genomic predictors; genomic profiles; improved; inhibitor/antagonist; insight; instructor; interest; killings; melanoma; methyl group; molecular targeted therapies; mortality; mouse model; new therapeutic target; novel; novel therapeutics; patient subsets; programs; small molecule inhibitor; snRNP Structural Core Protein; targeted agent; tenure track; therapeutic evaluation; therapeutic target; tumor

PROJECT SUMMARY The identification of novel cancer susceptibilities and genomic features predictive of those vulnerabilities can lead to new targeted therapeutic strategies. For example, activating mutations in BRAF or EGFR predict sensitivity to small molecule inhibitors of these proteins that demonstrate improved efficacy and favorable side effect profiles compared to standard cytotoxic chemotherapies in melanoma and non-small cell lung cancers, respectively. While immunotherapies have recently demonstrated dramatic clinical activity in some cancers, thus far these agents benefit only a subset of patients. As a result, targeted agents will remain an important therapeutic modality in clinical oncology. Thus, it is critical to incorporate comprehensive genomic profiling of cancers with functional studies to identify novel cancer vulnerabilities attributable to specific genomic features. Towards this end, we have found that cancer cell lines harboring a highly-recurrent genomic alteration (present in melanoma, non-small cell lung cancer, pancreatic cancer, and glioblastoma among others) are dependent on protein components of the methylosome, which catalyzes the transfer of methyl groups to arginine side- chains of multiple target proteins. This project seeks to further investigate the mechanistic basis and translational implications of this association through an integrative and collaborative approach. Specifically, I aim to identify therapeutic strategies to exploit this cancer dependency, to identify biological processes regulated by the methylosome that might serve as additional therapeutic targets, and to identify cellular effectors sufficient to compensate for this dependency on the methylosome. I am currently an Instructor of Medicine affiliated with the Division of Thoracic Oncology at Dana-Farber Cancer Institute. Over 75% of my time is devoted to my research interests under the mentorship of Levi Garraway at Dana-Farber Cancer Institute and the Broad Institute, with the remainder dedicated to clinical practice. My goal is to successfully transition to a tenure-track position as an independent investigator. To achieve this, I am seeking a K08 award to provide support for an additional period of mentored research to gain experience with methyltransferase biology, the use of mouse model systems for preclinical testing of therapeutic strategies, computational and statistical methodologies necessary for the analysis of large biological datasets, and functional genomic approaches necessary to achieve my immediate research goals. Under the guidance of a distinguished mentorship and advisory committee, I will have access to the resources and support necessary to establish a successful independent research program focusing on the identification and characterization of genetic determinants of cancer susceptibility and drug resistance in an effort to develop and refine therapeutic strategies for refractory cancers.

项目摘要 鉴定新的癌症敏感性和基因组特征可以预测这些脆弱性 导致新的有针对性的治疗策略。例如，在BRAF或EGFR中激活突变预测 对这些蛋白质的小分子抑制剂的敏感性，这些蛋白具有提高功效和有利的侧面 与黑色素瘤和非小细胞肺癌中的标准细胞毒性化学疗法相比，效应谱相比 分别。虽然免疫疗法最近在某些癌症中表现出戏剧性的临床活动，但 到目前为止，这些药物仅受益于一部分患者。结果，目标代理将仍然是重要的 临床肿瘤学中的治疗方式。因此，至关重要的是结合全面的基因组分析 具有功能研究的癌症，以鉴定可归因于特定基因组特征的新型癌症脆弱性。 为此，我们发现携带高度转换基因组改变的癌细胞系（目前 在黑色素瘤中，非小细胞肺癌，胰腺癌和胶质母细胞瘤等是依赖性的 在甲基甲基体的蛋白质成分上，该成分催化甲基向精氨酸侧的转移 多种靶蛋白的链。该项目旨在进一步研究机械基础和 通过综合和协作的方法对这种关联的翻译含义。具体来说，我 旨在确定利用这种癌症依赖性的治疗策略，以识别生物学过程 由甲基体调节，可能用作其他治疗靶标，并鉴定细胞 效应子足以补偿这种对甲基体的依赖性。 我目前是Dana-Farber Cancer胸部肿瘤学系的医学讲师 研究所。在Levi Garraway的指导下，我超过75％的时间致力于我的研究兴趣 Dana-Farber癌症研究所和Broad Institute，其余专门致力于临床实践。我的 目标是成功地过渡到终身轨道，成为独立研究者。为此，我 我正在寻求K08奖，以支持额外的指导研究以获得经验 使用甲基转移酶生物学，使用小鼠模型系统用于治疗的临床前测试 分析大型生物数据集所需的策略，计算和统计方法论， 以及实现我的直接研究目标所必需的功能基因组方法。在指导下 在一个杰出的指导和咨询委员会中，我将获得资源和支持 建立成功的独立研究计划所必需的，重点是标识和 表征癌症易感性和耐药性的遗传决定因素，以发展和 改善难治性癌症的治疗策略。