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: 10269645
• 负责人: Kenneth P Nephew
• 金额: $ 37.66万
• 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/10269645
• 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; 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/antagonist; 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.

摘要