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，有助于癌症的发展。免疫检查点 阻断（ICB）对某些患者有效，45-60%的患者对ICB无反应， 这些试剂的使用受到其毒性和/或获得性抗性的限制。迫切需要 针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癌症合成致死靶标。这一发现引发了 关于WRN如何保护MSI癌症免受DNA双链断裂的问题 以及实施WRN抑制治疗MSI癌症的最佳策略是什么。项目的目标是 为了解决这些问题，我们首先要验证我们的假设，即WRN需要展开 在MSI细胞中特异性富集的二级DNA结构（Aim 1）。此外，我们将 探索MSI背景下WRN的结构/功能关系，目的是识别 为药物发现工作提供信息的重要区域（目标2）。我们的初步数据还表明， WRN抑制诱导MSI细胞中的TNFα转录应答。这些结果启发了 我们的假设是，WRN缺失后的DNA损伤触发了先天免疫， 在MSI癌症中的反应（Aim 3）。通过整合功能基因组学、生物化学技术、 DNA修复生物学和体内建模，我们试图定义潜在的机制， 依赖MSI细胞中的WRN存活，促进WRN抑制剂的合理设计，和 促进MSI癌症的新联合疗法的开发。 我是一名医学肿瘤学家，具有功能基因组学和DNA修复生物学的背景。我 作为一名医生科学家的长期目标是领导一个基础/转化实验室，研究如何 癌症容忍受损的DNA修复途径和在这种情况下出现的脆弱性。我 将主要由Broad研究所和Dana-Farber癌症研究所的Adam Bass博士指导 院此外，我的科学咨询委员会由Alan D 'Andrea博士组成， Raymond Monnat，Matthew Meyerson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Andre Nussenzweig博士和泰勒杰克博士的合作， 重点培训和职业发展计划，拟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。

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.