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: 10670095
• 负责人: John Dubach
• 金额: $ 37.49万
• 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/10670095
• 关键词: Affinity; Amaze; BRCA mutations; Binding; Biological Markers; Biology; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Chromatin; Clinical; Clinical Trials; Combined Modality Therapy; Complex; 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; Pathway interactions; Patients; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Predisposition; Property; Protein Dynamics; Proteins; Role; Site; Techniques; Testing; Toxic effect; Work; Xenograft Model; Xenograft procedure; cancer therapy; clinical application; clinical efficacy; drug distribution; effective therapy; efficacy evaluation; homologous recombination; inhibitor; inhibitor therapy; 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）是涉及多个方面的酶家族， 细胞功能，包括DNA损伤修复（DDR）和染色质稳定性，以及其他沿着 才刚刚被发现PARP在DDR中的重要性，特别是非同源性 末端连接，使其成为DDR缺陷的癌症的理想治疗靶点。 突出。PARP的临床靶向首先在携带BRCA突变的患者中进行， 因此在同源重组中存在缺陷，其中PARP抑制是合成致死的。 尽管有效，但PARP抑制剂（PARPi）并没有证明如所希望的那样具有开创性， 几种抵抗机制和复员方案的复杂性。目前已批准3个 PARP抑制剂用于治疗卵巢癌患者和另外两种晚期临床 审判然而，我们对PARP疗效的分子生物学基础的理解仍然存在， 有限公司有趣的是，敲除PARP不会产生PARP所发现的细胞杀伤力 抑制剂，这是最近解释的发现，PARP抑制剂陷阱PARP的网站 DNA损伤。然而，即使它们结合到相同的蛋白质口袋中， 由于PARP抑制剂的亲和力较低，一些PARP抑制剂是更有效的捕获剂，原因尚不清楚。 因此，PARP抑制剂通过捕获和酶抑制两者起作用。我们 细胞系应答数据库的初步分析表明， 对不同PARP抑制剂的敏感性，一些细胞系对低捕获更敏感 抑制剂和其他更敏感的高捕获抑制剂。确定的机制 差异PARP抑制剂敏感性将提供洞察临床选择之间的 PARP抑制剂，以推动更有效的治疗。在这里，我们将讨论三个具体目标 通过单细胞蛋白表达和动力学的新方法：1）确定PARPi- 选择最佳PARPi治疗的细胞反应的特定驱动因素，2）阐明 PARPi敏感性的分子机制，以优化联合治疗，以及3）最佳配对 PARPi以提高疗效并将毒性降至最低。解析PARP抑制剂的作用机制 有效性将使最佳临床使用和组合试验设计成为可能。我们希望能确定 每种临床PARP抑制剂的反应生物标志物，其将指导临床选择 PARPi治疗。