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: 10678850
• 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/10678850
• 关键词: ATR gene; Advisory Committees; BRCA deficient; Cancer Biology; Cell Cycle Progression; Cell physiology; Cellular biology; 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; Mediating; Mentors; Mentorship; Methods; Methylation; Modeling; Molecular Biology; Morbidity - disease rate; Mus; Mutation; Nature; Pathway interactions; Pediatrics; Phenotype; Phosphotransferases; Physicians; Poly(ADP-ribose) Polymerase Inhibitor; 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; carcinogenesis; 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/摘要 候选人Vasquez博士是耶鲁大学医学院的儿科助理教授， 耶鲁大学癌症中心癌症免疫学项目和耶鲁大学免疫肿瘤学培训的学员 程序.该提案的重点是DNA损伤和肿瘤免疫原性之间的联系， 为Vasquez博士提供必要的研究技能，例如询问DNA修复和免疫的方法。 途径和同基因小鼠模型的临床前研究。瓦斯奎兹博士将在 在癌症免疫学、癌症细胞和分子生物学、计算生物学和早期临床 试验设计他还将参加地方和国家癌症生物学和免疫学会议。博士 Vasquez的主要导师Ranjit Bindra博士是一位物理学家兼科学家，拥有R 01资助的研究实验室 也是利用DNA修复途径治疗癌症的专家。瓦斯奎兹医生的顾问委员会 包括Hideho Okada博士，一位临床前神经胶质瘤免疫治疗研究专家。 加里库普弗，一位在癌症基因组不稳定性研究方面有专长的医生兼科学家，和大卫博士 Hafler博士是一位物理学家兼科学家，也是神经免疫学的先驱。这个多学科的导师团队，沿着 凭借耶鲁大学的优秀科学资源，将使Vasquez博士能够获得更多 指导的研究经验，使他可能成为一个独立资助的调查员。 研究项目。迄今为止，免疫检查点抑制剂（ICi）在治疗糖尿病中无效。 神经胶质瘤，很大程度上是由于免疫学上的“冷”微环境和低数量的新抗原。我们 一个研究小组最近发现，在胶质瘤中常见的IDH 1/2突变， 重组（HR）缺陷，并赋予对DNA损伤反应抑制剂（DDRi）的敏感性，例如聚 （ADP-核糖）聚合酶（PARP）抑制剂和共济失调毛细血管扩张症和Rad 3相关（ATR）激酶 抑制剂的新出现的证据表明，遗传性或获得性DDR缺陷会增加肿瘤免疫原性 通过DNA损伤诱导的免疫识别途径的激活。因此，中心假设 我的一个建议是突变IDH 1/2诱导的DNA修复缺陷可以用PARP和ATR激酶来开发 抑制以诱导宿主和癌细胞内在免疫活化并改善ICi应答 免疫原性差的神经胶质瘤在目标1中，我们将进行一系列体外和体内研究，以测试 PARP和ATR联合抑制对IDH 1/2突变型胶质瘤的潜在疗效，并探索DNA修复 导致这种合成致命性的机制。在目标2中，我们将探讨免疫介导的机制 的DDRi合成致死性，并确定肿瘤内在和宿主依赖性免疫调节作用的DDRi的合成致死性， 组合PARP和ATR抑制。在目标3中，我们将确定PARP和ATR抑制，单独或联合 组合改善了体内对抗PD-1的应答。