Optimizing PARP inhibitor therapy through novel approaches to resolve the molecular mechanisms of response

通过新方法优化 PARP 抑制剂治疗以解决分子反应机制

• 批准号: 10212344
• 负责人: John Dubach
• 金额: $ 38.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212344
• 关键词: Address; Affinity; BRCA mutations; Binding; Biological Markers; Biology; Cell Line; Cell physiology; Cells; Chromatin; Clinical; Clinical Trials; Combined Modality Therapy; DNA Damage; DNA Repair; Data; Databases; Defect; Development; Dose; Dose-Limiting; Enzymes; Family; Goals; Heterogeneity; Knock-out; Malignant Neoplasms; Malignant neoplasm of ovary; Molecular; Molecular Biology; Nonhomologous DNA End Joining; Outcome; Ovarian; Pathway interactions; Patient Rights; Patients; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerases; Predisposition; Property; Protein Dynamics; Proteins; Role; Site; Testing; Toxic effect; Work; Xenograft Model; Xenograft procedure; cancer therapy; clinical application; clinical efficacy; drug distribution; effective therapy; homologous recombination; inhibitor/antagonist; insight; novel; novel strategies; protein expression; resistance mechanism; response; response biomarker; single cell analysis; single cell proteins; therapeutic target; trial design; tumor

Poly(ADP-ribose) polymerases (PARP) are a family of enzymes involved with multiple facets of cellular function including DNA damage repair (DDR) and chromatin stability, along with others that are just being discovered. The importance of PARP in DDR, specifically non-homologous end joining, makes it an ideal therapeutic target in cancer where DDR deficiencies are prominent. Clinical targeting of PARP was first performed in patients harboring BRCA mutations, and thus defects in homologous recombination, where PARP inhibition is synthetically lethal. Although effective, PARP inhibitors (PARPi) did not prove as ground breaking as hoped due to several resistance mechanisms and the complexity of DDR. Currently there are 3 approved PARP inhibitors for treatment of patient with ovarian cancer and two more in late stage clinical trials. However, our understanding of molecular biology underlying PARP efficacy remains limited. Intriguingly, knocking out PARP does not produce the cellular lethality found with PARP inhibitor, which was recently explained by the discovery that PARP inhibitors trap PARP to sites of DNA damage. However, even though they bind into the same protein pocket and have similar affinities, some PARP inhibitors are much more potent trappers, the reason remains unknown. Thus, PARP inhibitors function through both trapping and and enzymatic inhibition. Our preliminary analysis of cell line response databases demonstrates wide differences in cell line susceptibility to different PARP inhibitors, with some cell lines more sensitive to low trapping inhibitors and other more sensitive to high trapping inhibitors. Determining the mechanisms of differential PARP inhibitor sensitivity would provide insight into clinical selection among the PARP inhibitors to drive more effective therapies. Here we will address three specific aims through novel approaches of single cell protein expression and dynamics: 1) determine PARPi- specific drivers of cellular response to select optimal PARPi treatment, 2) elucidate the molecular mechanism of PARPi sensitivity to optimize combination therapy, and 3) optimally pair PARPi to increase efficacy and minimize toxicity. Resolving the mechanisms of PARP inhibitor efficacy will enable optimal clinical use and combination trial design. We expect to determine biomarkers of response for each of the clinical PARP inhibitors that will guide clinical selection of PARPi treatment.

聚（adp -核糖）聚合酶（PARP）是一个涉及多个方面的酶家族