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.

项目总结