Advancing WRN as a synthetic lethal target for microsatellite unstable cancers

项目摘要 微卫星不稳定性(MSI)，一类由DNA损伤引起的遗传超突变 错配修复，有助于各种癌症的发展。虽然免疫检查站 阻断(ICB)对某些患者有效，45%-60%的患者对ICB无效， 这些药物的使用可能受到其毒性和/或获得性抗药性的限制。当务之急 对这一大类癌症的进一步治疗激发了我们识别RecQ的努力 解旋酶WRN作为MSI癌症的合成致死靶点。这一发现提出了根本的 关于WRN如何保护MSI癌细胞免受DNA双链断裂的质疑 实施WRN抑制治疗MSI癌的最佳策略是什么？这个项目寻求 为了解决这些问题，首先测试我们的假设，即WRN需要解除 在MSI细胞中特异富含的二级DNA结构(目标1)。此外，我们还将 在MSI的背景下探索WRN的结构/功能关系，目标是确定 为药物发现工作提供信息的关键区域(目标2)。我们的初步数据也表明 抑制WRN可诱导微卫星细胞的肿瘤坏死因子α转录反应。这些结果启发了我们 我们的假设是WRN耗尽后的DNA损伤触发了一种先天免疫 MSI癌症的反应(目标3)。通过整合功能基因组学，生化技术， DNA修复生物学，以及活体建模，我们试图定义 依赖WRN在MSI细胞中生存，促进WRN抑制剂的合理设计，以及 推动MSI癌新综合疗法的开发。 我是一名内科肿瘤学家，有功能基因组学和DNA修复生物学的背景。我的 作为一名内科科学家的长期目标是领导一个基础/翻译实验室研究如何 癌症耐受受损的DNA修复途径和在此背景下出现的脆弱性。我 将主要由布罗德研究所的亚当·巴斯博士和达纳-法伯癌症教授指导 研究所。此外，我的科学顾问委员会由艾伦·丹安德里亚博士组成， 雷蒙德·莫纳特、马修·迈尔森和大卫·芭比将帮助指导我的科学和职业生涯 发展。再加上与安德烈·努森茨韦格博士和泰勒·杰克博士的合作， 有重点的培训和职业发展计划，建议的培训计划将帮助我建立 作为一名独立调查员开始我的职业生涯的势头。

Project Summary Microsatellite instablility (MSI), a class of genetic hypermutability arising from impaired DNA mismatch repair, contributes to development to types of cancers. While immune checkpoint blockade (ICB) is effective for some patients, 45-60% of patients do not response to ICB and the use of these agents can be limited by their toxicity and/or acquired resistance. The pressing need for further therapies against this large class of cancers inspired our efforts identifying the RecQ helicase WRN as a synthetic lethal target for MSI cancers. This discovery raises fundamental questions about how WRN functions to protect the MSI cancers from DNA double strand breaks and what is the best strategy to implement WRN inhibition to treat MSI cancers. This project seeks to address these questions by first testing our hypothesis that WRN is required to unwind secondary DNA structures that are specifically enriched in MSI cells (Aim 1). Furthermore, we will explore the structure/function relationship of WRN in the context of MSI with a goal of identifying essential regions to inform drug discovery efforts (Aim 2). Our preliminary data also demonstrated that WRN inhibition induces a TNFα transcriptional response in MSI cells. These results inspired our hypothesis that the DNA damage following WRN depletion triggers an innate immune response in MSI cancers (Aim 3). By integrating functional genomics, biochemical techniques, DNA repair biology, and in vivo modeling, we seek to define the mechanism underlying the dependence upon WRN in MSI cells for survival, facilitate rational design of WRN inhibitors, and promote development of new combination therapies for MSI cancers. I am a medical oncologist with a background in functional genomics and DNA repair biology. My long-term goal as a physician-scientist is to lead a basic/translational laboratory studying how cancers tolerate impaired DNA repair pathways and the vulnerabilities that arise in this context. I will be primarily mentored by Dr. Adam Bass at the Broad Institute and Dana-Farber Cancer Institute. Furthermore, my scientific advisory committee composed of Drs. Alan D’Andrea, Raymond Monnat, Matthew Meyerson, and David Barbie will help guide my scientific and career development. Coupled with collaborations with Drs. Andre Nussenzweig and Tyler Jacks, a focused training and career developmental plan, the proposed training plan will help me build the momentum to launch my career as an independent investigator.