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: 10696950
• 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/10696950
• 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; Interferons; Knock-out; Laboratory Study; 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; 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; skills

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.

项目概要 微卫星不稳定性 (MSI)，一类由 DNA 受损引起的遗传超突变性 错配修复有助于癌症类型的发展。 阻断（ICB）对某些患者有效，45-60%的患者对ICB没有反应， 这些药物的使用可能受到其毒性和/或获得性耐药性的限制。 针对这一大类癌症的进一步治疗激发了我们确定 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性的建议。 关于 WRN 如何发挥作用来保护 MSI 癌症免受 DNA 双链断裂的问题 该项目寻求实施 WRN 抑制来治疗 MSI 癌症的最佳策略是什么。 为了解决这些问题，首先测试我们的假设：WRN 需要展开 MSI 细胞中特别富集的二级 DNA 结构（目标 1）。 探索 MSI 背景下 WRN 的结构/功能关系，目的是识别 我们的初步数据也证明了为药物发现工作提供信息的重要区域（目标 2）。 WRN 抑制会在 MSI 细胞中诱导 TNFα 转录反应。这些结果启发了我们。 我们的假设是 WRN 耗竭后的 DNA 损伤会触发先天免疫 MSI 癌症的反应（目标 3）。 DNA 修复生物学和体内建模，我们寻求定义潜在的机制 MSI细胞的生存依赖于WRN，促进WRN抑制剂的合理设计，以及 促进 MSI 癌症新联合疗法的开发。 我是一名肿瘤内科医生，拥有功能基因组学和 DNA 修复生物学背景。 作为一名医师科学家的长期目标是领导一个基础/转化实验室研究如何 癌症能够耐受受损的 DNA 修复途径以及在这种情况下出现的脆弱性。 主要由 Broad Institute 和 Dana-Farber Cancer 的 Adam Bass 博士指导 此外，我的科学顾问委员会由 Alan D’Andrea 博士组成。 雷蒙德·莫纳特、马修·迈耶森和大卫·芭比将帮助指导我的科学和职业生涯 加上与 Andre Nussenzweig 博士和 Tyler Jacks 博士的合作。 有针对性的培训和职业发展计划，所提出的培训计划将帮助我建立 开启我作为一名独立调查员的职业生涯的动力。