Targeting the DNA damage response with PARP and ATR inhibition to potentiate cytotoxicity and improve efficacy of immune checkpoint blockade in IDH mutant gliomas

通过 PARP 和 ATR 抑制来靶向 DNA 损伤反应，以增强细胞毒性并提高 IDH 突变神经胶质瘤中免疫检查点阻断的功效

• 批准号: 10457266
• 负责人: JUAN C VASQUEZ
• 金额: $ 23.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457266
• 关键词: ATR gene; Advisory Committees; BRCA deficient; Cancer Biology; Cell Cycle Progression; Cell physiology; Citric Acid Cycle; Clinical Trials Design; Computational Biology; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Defect; Dioxygenases; Double Strand Break Repair; Evaluation; Family; Fumarates; Funding; Genes; Genetic; Genomic Instability; Glioblastoma; Glioma; Goals; Grant; Histones; Hypermethylation; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunocompetent; Immunocompromised Host; Immunologics; Immunooncology; Immunotherapy; In Vitro; Inherited; Interferons; Isocitrate Dehydrogenase; Laboratories; Laboratory Research; Link; Literature; Lysine; Malignant Neoplasms; Masks; Mediating; Mentors; Mentorship; Methods; Modeling; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Mutation; Nature; Pathway interactions; Pediatrics; Phenotype; Phosphotransferases; Physicians; Poly(ADP-ribose) Polymerases; Production; Publishing; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Resources; Scientist; Series; Signal Transduction; Site; Stimulator of Interferon Genes; Succinates; T-Cell Depletion; Testing; Time; Training Programs; Translational Research; Triplet Multiple Birth; Tumor Immunity; Up-Regulation; Yale Cancer Center; anti-PD-1; anti-PD1 therapy; cancer cell; cancer therapy; checkpoint inhibition; clinical efficacy; comparative efficacy; cytotoxicity; early phase clinical trial; experience; experimental study; homologous recombination; immune activation; immune checkpoint blockade; immunogenic; immunogenic cell death; immunogenicity; immunoregulation; improved; in vivo; inhibitor; innate immune pathways; kinase inhibitor; knockout gene; medical schools; member; metaplastic cell transformation; mouse model; multidisciplinary; mutant; neoantigens; neuroimmunology; novel; pre-clinical; preclinical study; preclinical trial; professor; programmed cell death ligand 1; programs; recruit; repaired; response; skills; small molecule; success; symposium; synergism; translational medicine; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Candidate. Dr. Vasquez is an Assistant Professor of Pediatrics at the Yale School of Medicine and a member of the Yale Cancer Center Cancer Immunology Program and trainee in the Yale Immuno-Oncology Training Program. This proposal is focused on the link between DNA damage and tumor immunogenicity and will provide Dr. Vasquez with essential research skills, such as methods for interrogating DNA repair and immune pathways and pre-clinical studies with syngeneic mouse models. Dr. Vasquez will take advanced coursework in cancer immunology, cellular and molecular biology of cancer, computational biology, and early phase clinical trial design. He will also participate in local and national cancer biology and immunology conferences. Dr. Vasquez’s primary mentor, Dr. Ranjit Bindra, is a physician-scientist with an R01-funded research laboratory and an expert in leveraging DNA repair pathways in the treatment of cancer. Dr. Vasquez’s advisory committee includes Dr. Hideho Okada, a physician-scientist and expert in preclinical glioma immunotherapy research, Dr. Gary Kupfer, a physician-scientist with expertise in the study of genomic instability in cancer and Dr. David Hafler, a physician-scientist and pioneer in neuro-immunology. This multidisciplinary mentorship team, along with the outstanding scientific resources available at Yale, will allow Dr. Vasquez to acquire additional mentored research experience so that he may become an independently funded investigator. Research Project. Immune checkpoint inhibitors (ICi) have, thus far, been ineffective in the treatment of glioma, largely due to the immunologically “cold” microenvironment and the low number of neoantigens. Our group recently discovered that IDH1/2 mutations, which are common in gliomas, induce homologous recombination (HR) defects and confer sensitivity to DNA damage response inhibitors (DDRi), such as poly (ADP-ribose) polymerase (PARP) inhibitors and Ataxia telangiectasia and Rad3-related (ATR) kinase inhibitors. Emerging evidence shows that inherited or acquired DDR defects increase tumor immunogenicity through DNA damage-induced activation of immune recognition pathways. Therefore, the central hypothesize of my proposal is that mutant IDH1/2-induced DNA repair defects can be exploited with PARP and ATR kinase inhibition to induce host and cancer cell-intrinsic immune activation and improve ICi response in otherwise poorly immunogenic gliomas. In Aim 1, we will perform a series of in vitro and in vivo studies to test the potential efficacy of combined PARP and ATR inhibition against IDH1/2-mutant glioma and explore DNA repair mechanisms contributing to this synthetic lethality. In Aim 2, we will probe the immune-mediated mechanisms of DDRi synthetic lethality and define the tumor-intrinsic and host-dependent immunomodulatory effects of combined PARP and ATR inhibition. In Aim 3, we will determine whether PARP and ATR inhibition, alone or in combination, improves the response to anti-PD-1 in vivo.

项目总结/文摘