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

项目摘要/摘要 候选人。瓦斯克斯博士是耶鲁大学医学院儿科学助理教授，也是 耶鲁癌症中心癌症免疫学项目和耶鲁免疫肿瘤学培训的实习生 程序。这项建议的重点是DNA损伤和肿瘤免疫原性之间的联系，并将 为巴斯克斯博士提供基本的研究技能，如询问DNA修复和免疫的方法 同基因小鼠模型的途径和临床前研究。瓦斯克斯博士将选修高级课程 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。Dr。 Vasquez的主要导师Ranjit Bindra博士是一名内科科学家，在R01资助的研究实验室工作 以及在癌症治疗中利用DNA修复途径的专家。瓦斯克斯博士的咨询委员会 包括内科科学家、临床前脑胶质瘤免疫治疗研究专家冈田英浩博士。 加里·库普费尔，一位在癌症基因组不稳定性研究方面拥有专业知识的内科科学家和大卫博士 哈夫勒是一位内科科学家和神经免疫学的先驱。这个多学科的指导团队，以及 凭借耶鲁大学现有的杰出科学资源，瓦斯克斯博士将获得更多 指导他的研究经验，使他可以成为一名独立资助的研究人员。 研究项目。到目前为止，免疫检查点抑制剂(Ici)在治疗黑色素瘤方面是无效的。 胶质瘤，很大程度上是由于免疫“寒冷”的微环境和新抗原的数量较少。我们的 研究小组最近发现，在胶质瘤中常见的IDH1/2突变会导致同源基因 重组(HR)缺陷和对DNA损伤反应抑制物(DDRI)的敏感性 (ADP-核糖)聚合酶(PARP)抑制剂与共济失调毛细血管扩张症和RAD3相关(ATR)激酶 抑制剂。新的证据表明，遗传或获得性DDR缺陷增加了肿瘤的免疫原性 通过DNA损伤诱导免疫识别通路的激活。因此，核心假设是 我的建议之一是，突变的IDH1/2诱导的DNA修复缺陷可以用PARP和ATR激酶来利用 抑制诱导宿主和癌细胞的内源性免疫激活并改善ICI反应 免疫原性差的胶质瘤。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IDH1/2突变型胶质瘤的疗效及DNA修复探讨 导致这种综合致命性的机制。在目标2中，我们将探讨免疫介导的机制。 的合成杀伤力，并确定肿瘤固有的和宿主依赖的免疫调节作用 PARP和ATR联合抑制。在目标3中，我们将确定单独或联合抑制PARP和ATR 联合应用，可提高体内对抗PD-1抗体的反应。

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.