Linking Epigenetic-Therapy Induction of Inflammasome Signaling to Generation of a BRCAness Phenotype

将表观遗传治疗诱导炎症体信号传导与 BRCAness 表型的生成联系起来

• 批准号: 10470367
• 负责人: Kenneth P Nephew
• 金额: $ 38.92万
• 依托单位: CORIELL INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470367
• 关键词: Acute Myelocytic Leukemia; Address; BRCA deficient; BRCA mutations; BRCA1 Mutation; Biological Markers; Biopsy; Cancer Etiology; Cancer Patient; Cell Death; Cells; Chromosomal Rearrangement; Clinic; Clinical; Combined Modality Therapy; Complex; DNA Damage; DNA Repair; DNA Single Strand Break; Data; Defect; Diagnosis; Dose; Double Strand Break Repair; Double-Stranded RNA; Funding; Generations; Genes; Genetic Transcription; Goals; Grant; Immune; Immune response; Immune signaling; Immunocompetent; Impairment; In Vitro; In complete remission; Inflammasome; Interferons; Knowledge; Laboratory Study; Lead; Link; Maintenance Therapy; Malignant neoplasm of ovary; Mediating; Metastatic breast cancer; Mission; Modeling; Molecular; Mus; Mutate; Neoadjuvant Therapy; Non-Small-Cell Lung Carcinoma; PARP inhibition; Pathogenesis; Pathway interactions; Patients; Persons; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Platinum; Progression-Free Survivals; Public Health; Reactive Oxygen Species; Relapse; Reporting; Research; Resistance; Risk; Sampling; Scientific Advances and Accomplishments; Serous; Signal Transduction; Site; TNF gene; Testing; The Cancer Genome Atlas; Therapeutic; Treatment Efficacy; Tumor Immunity; Viral; Woman; anticancer research; base; cancer biomarkers; cancer subtypes; checkpoint therapy; chemotherapy; cohort; cytotoxicity; ds-DNA; epigenetic therapy; gene repair; homologous recombination; improved outcome; in vivo; inhibitor; insight; malignant breast neoplasm; mutational status; novel; novel therapeutic intervention; partial response; phase 2 study; phase II trial; preclinical study; repaired; response; synergism; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

Abstract PARP inhibitor (PARPi) resistance remains a clinical hurdle, with therapy limited to breast and ovarian cancer (OC) patients with BRCA mutations, and some activity seen in OC patients with intact BRCA. Our preclinical studies demonstrate that combining a hypomethylating agent (DNMT inhibitor) and the novel PARPi talazoparib inhibited tumor growth regardless of BRCA mutation status in both breast and OC by inducing inflammasome signaling that generates a BRCAness phenotype, synergistically causing cancer cell death. This led to a dose- finding phase I clinical trial in TNBC funded by Pfizer and Astex and we propose a phase II trial combining a DNMTi and PARPi in breast and OC patients with intact BRCA that includes correlative analyses in serial patient samples and mechanistic studies in vitro and in vivo using immunocompetent mice treated with DNMTi-PARPi combination therapy. The overall goal of this proposal is to expand the benefit of PARPi therapy to a much larger group of patients and further dissect mechanisms of PARPi cytotoxicity and resistance. Our central hypothesis is epigenetic therapy-inducing inflammasome signaling generates BRCAness that enhances the efficacy of PARPi in BRCA-proficient TNBC and OC. We propose three aims. Aim 1: To test the hypothesis that combining DNMTi + PARPi generates STING-dependent IFN and inflammasome signaling leading to a BRCAness phenotype that increases anti-tumor immunity in the tumor microenvironment. We hypothesize that DNMTi + PARPi activates STING and inflammasome signaling leading to BRCAness in BRCA- proficient TNBC and OC. We will conduct mechanistic studies of factors linking immune signaling to BRCAness phenotype, functional analysis of immune subsets in immune-competent mice treated with PARPi-DNMTi combination. Aim 2: To test the hypothesis that DNMTi in combination with PARPi activate reactive oxygen species (ROS)-mediated DNA damage leading to cell death in BRCA-proficient TNBC and OC. We will investigate how ROS generated by DNMTi-PARPi combination enhances DNA damage response (DDR) signaling, induces STING activation and enhances immune responses against TNBC and OC tumors using immune-competent mice. Aim 3: To assess the clinical activity of DNMTi-PARPi combination in TNBC and OC patients in phase I/II clinical trials. After completing the ongoing phase 1, we propose a phase II study in two patient cohorts (one TNBC, one OC), serial tumor biopsies and circulating correlatives to test mechanistic hypotheses derived from our preclinical studies in patient samples. We will probe modulation of BRCAness- HRD, DDR genes, ROS signaling, immune signaling genes and functional analysis of immune subsets. Impact: Combining DNMTi-PARPi to induce a novel link between STING-mediated immune signaling and direct induction of a BRCAness-HRD phenotype represents a potentially important treatment advance and therapeutic option for women diagnosed with TNBC and OC who lack BRCA mutations and for which there is an urgent clinical need. Efficacy may be further enhanced by including immune checkpoint therapy to this treatment strategy.

抽象的 PARP 抑制剂 (PARPi) 耐药性仍然是临床障碍，治疗仅限于乳腺癌和卵巢癌 (OC) 具有 BRCA 突变的患者，以及在具有完整 BRCA 的 OC 患者中观察到的一些活性。我们的临床前 研究表明，结合低甲基化剂（DNMT 抑制剂）和新型 PARPi Talazoparib 无论乳腺和 OC 中的 BRCA 突变状态如何，通过诱导炎性体抑制肿瘤生长 产生 BRCAness 表型的信号传导，协同导致癌细胞死亡。这导致剂量- 发现 TNBC 的 I 期临床试验由辉瑞 (Pfizer) 和 Astex 资助，我们提出了一项结合以下各项的 II 期试验： 具有完整 BRCA 的乳腺癌和 OC 患者中的 DNMTi 和 PARPi，包括连续患者的相关分析 使用经 DNMTi-PARPi 处理的免疫活性小鼠进行体外和体内样品和机制研究 联合疗法。该提案的总体目标是将 PARPi 疗法的益处扩大到更多 更多的患者群体并进一步剖析 PARPi 细胞毒性和耐药性的机制。我们的中央 假设是表观遗传治疗诱导的炎性体信号传导产生 BRCA 性，从而增强 PARPi 在 BRCA 熟练的 TNBC 和 OC 中的功效。我们提出三个目标。目标 1：检验假设 结合 DNMTi + PARPi 产生 STING 依赖性 IFN 和炎性体信号传导，从而导致 一种 BRCAness 表型，可增加肿瘤微环境中的抗肿瘤免疫力。我们 假设 DNMTi + PARPi 激活 STING 和炎性体信号传导导致 BRCA- 精通TNBC和OC。我们将对免疫信号传导与 BRCA 相关的因素进行机制研究 PARPi-DNMTi 治疗的免疫活性小鼠免疫亚群的表型、功能分析 组合。目标 2：检验 DNMTi 与 PARPi 结合激活反应性的假设 氧 (ROS) 介导的 DNA 损伤导致 BRCA 熟练的 TNBC 和 OC 细胞死亡。 我们将研究 DNMTi-PARPi 组合产生的 ROS 如何增强 DNA 损伤反应 (DDR) 信号传导，诱导 STING 激活并增强针对 TNBC 和 OC 肿瘤的免疫反应 具有免疫能力的小鼠。目标 3：评估 DNMTi-PARPi 组合在 TNBC 和 处于 I/II 期临床试验中的 OC 患者。完成正在进行的第一阶段后，我们建议进行第二阶段研究 两个患者队列（一名 TNBC，一名 OC）、连续肿瘤活检和循环相关物以测试机制 假设源自我们对患者样本的临床前研究。我们将探讨 BRCAness 的调节 - HRD、DDR基因、ROS信号、免疫信号基因和免疫子集的功能分析。影响： 结合 DNMTi-PARPi 诱导 STING 介导的免疫信号传导与直接诱导之间的新联系 BRCAness-HRD 表型的研究代表了潜在的重要治疗进展和治疗选择 被诊断患有 TNBC 和 OC 且缺乏 BRCA 突变且临床急需的女性。 通过将免疫检查点疗法纳入该治疗策略，可以进一步增强疗效。