Advancing WRN as a synthetic lethal target for microsatellite unstable cancers

推进 WRN 作为微卫星不稳定癌症的合成致死靶点

• 批准号: 10629636
• 负责人: Edmond Chan
• 金额: $ 23.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629636
• 关键词: Address; Advisory Committees; Affect; Apoptosis; Award; Bass; Biochemical; Biological Assay; Biology; Cell Cycle Arrest; Cell Survival; Cells; Cellular Assay; ChIP-seq; Clinical; Collaborations; Colon Carcinoma; Coupled; Cyclic GMP; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA Structure; DNA replication fork; Dana-Farber Cancer Institute; Data; Deletion Mutation; Dependence; Development; Dinucleoside Phosphates; Dinucleotide Repeats; Drug Design; Drug usage; Endometrial Carcinoma; Essential Genes; Funding; Genetic; Genetic Transcription; Genomics; Goals; Immunotherapy; Impairment; Inflammatory Response; Innate Immune Response; Institutes; Interferons; Knock-out; Laboratory Study; Lead; Length; Lysine; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Medical Oncologist; Mentors; Microsatellite Instability; Microsatellite Repeats; Mismatch Repair; Modeling; Molecular Biology; Mus; Mutate; Nuclear; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physicians; Play; Positioning Attribute; Post-Translational Protein Processing; Repetitive Sequence; Reporter; Research Personnel; Research Proposals; Resistance; Role; Scientist; Serine; Signal Transduction; Stimulator of Interferon Genes; Structure; Structure-Activity Relationship; TNF gene; Techniques; Testing; Therapeutic; Threonine; Toxic effect; Training; Translations; Tyrosine; WRN gene; antitumor effect; base; cancer cell; cancer type; career; career development; drug discovery; functional genomics; helicase; immune checkpoint blockade; in vivo Model; inhibitor; malignant stomach neoplasm; new combination therapies; novel; novel therapeutics; prevent; programmed cell death protein 1; programs; rational design; replication stress; response

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.

项目摘要 微卫星不稳定性（MSI），这是由DNA受损引起的一类遗传性超切的性能 不匹配维修，有助于开发癌症类型。而免疫检查点 封锁（ICB）对某些患者有效，有45-60％的患者对ICB不反应 这些药物的使用可能会受到其毒性和/或获得性抗性的限制。紧迫的需要 为了进一步针对这种大型癌症的疗法，我们的努力确定了RECQ 解旋酶WRN作为MSI癌的合成致死靶标。这一发现提高了基本 有关WRN如何保护MSI癌症免受DNA双链断裂的问题 实施WRN抑制以治疗MSI癌的最佳策略是什么？这个项目寻求 通过首先测试我们的假设，即WRN需要放松，以解决这些问题 特异性富集在MSI细胞中的次级DNA结构（AIM 1）。此外，我们会的 在MSI的背景下探索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基本区域（AIM 2）。我们的初步数据也证明了 该WRN抑制作用诱导MSI细胞中的TNFα转录反应。这些结果启发了 我们的假设是，WRN部署后的DNA损害触发了先天免疫 MSI癌症的反应（AIM 3）。通过整合功能基因组学，生化技术， DNA修复生物学和体内建模，我们寻求定义基础的机制 MSI细胞中对WRN的依赖性生存，促进WRN抑制剂的合理设计，并且 促进为MSI取消的新组合疗法的开发。 我是具有功能基因组学和DNA修复生物学背景背景的医学肿瘤学家。我的 作为身体科学家的长期目标是领导基本/转化实验室研究 癌症可以忍受受损的DNA修复途径以及在这种情况下出现的脆弱性。我 Broad Institute和Dana-Farber Cancer的Adam Bass博士将主要由Adam Bass指导 研究所。此外，我的科学咨询委员会由Drs组成。艾伦·德·安德里亚（Alan D'Andrea）， Raymond Monnat，Matthew Meyerson和David Barbie将帮助指导我的科学和职业 发展。再加上与Drs的合作。 Andre Nussenzweig和Tyler Jacks， 拟议的培训计划将重点培训和职业发展计划，将帮助我建立 势头启动我作为独立调查员的职业。