Mechanistic Dissection of an Arginine Methyltransferase Dependency in Cancer

项目摘要 识别新的癌症易感性和预测这些脆弱性的基因组特征， 导致新的靶向治疗策略。例如，BRAF或EGFR中的激活突变预测 对这些蛋白质的小分子抑制剂的敏感性， 在黑色素瘤和非小细胞肺癌中与标准细胞毒性化疗相比的效果概况， 分别虽然免疫疗法最近在一些癌症中表现出显著的临床活性， 到目前为止，这些药物仅使一部分患者受益。因此，靶向药物仍将是重要的 临床肿瘤学的治疗模式。因此，关键是要纳入全面的基因组分析， 癌症与功能研究，以确定新的癌症脆弱性归因于特定的基因组特征。 为此，我们已经发现，具有高度复发性基因组改变的癌细胞系（存在于癌细胞系中）， 在黑色素瘤、非小细胞肺癌、胰腺癌和胶质母细胞瘤等中）是依赖于 甲基体的蛋白质组分，其催化甲基转移到精氨酸侧- 多个靶蛋白的链。该项目旨在进一步研究机械基础， 通过整合和协作的方法，这种关联的翻译影响。我特别 目的是确定利用这种癌症依赖性的治疗策略， 由甲基化体调节，可能作为额外的治疗靶点，并确定细胞 足以补偿这种对甲基化体的依赖性的效应物。 我目前是达纳法伯癌症中心胸部肿瘤科的医学讲师 院我超过75%的时间都是在Levi Garraway的指导下致力于我的研究兴趣。 丹娜-法伯癌症研究所和布罗德研究所，其余致力于临床实践。我 目标是成功过渡到作为独立调查员的终身职位。为了实现这一点，我 我正在寻求一个K 08奖，以提供额外一段时间的指导研究，以获得经验的支持 与甲基转移酶生物学，使用小鼠模型系统进行临床前试验， 大型生物数据集分析所需的策略、计算和统计方法， 和功能基因组学方法来实现我的近期研究目标。为指导 一个杰出的指导和咨询委员会，我将有机会获得资源和支持， 有必要建立一个成功的独立研究计划，重点是识别和 癌症易感性和耐药性的遗传决定因素的表征， 完善难治性癌症的治疗策略。

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.