Project 2: Combination PARPi-BETi to Overcome PARPi Resistance

项目 2： PARPi-BETi 组合克服 PARPi 耐药性

• 批准号: 10713053
• 负责人: Haider Mahdi
• 金额: $ 45.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713053
• 关键词: 19p13; ATAC-seq; Address; BRCA1 gene; Biopsy; Bromodomains and extra-terminal domain inhibitor; Cancer Patient; Cell Cycle; ChIP-seq; Clinical; Combination Drug Therapy; DNA Damage; Data; Disease Resistance; Dose Limiting; Epithelial ovarian cancer; G2/M Checkpoint Pathway; Gene Expression; Genes; Impairment; M cell; Malignant Neoplasms; Malignant neoplasm of ovary; Maximum Tolerated Dose; Measures; Mitosis; Mitotic; Modeling; Mutation; Organoids; PARP inhibition; Pathway interactions; Patients; Pharmaceutical Preparations; Phase Ib Clinical Trial; Platinum; Play; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Prediction of Response to Therapy; Prognosis; Rationalization; Recurrence; Regimen; Resistance; Role; Safety; Sampling; Serous; TOPBP1 Gene; Testing; Time; Tissues; Toxic effect; Up-Regulation; biomarker driven; cancer cell; clinical application; clinical predictors; efficacy evaluation; epigenetic therapy; genome-wide; genomic locus; homologous recombination; improved outcome; inhibitor therapy; innovation; novel; novel therapeutics; objective response rate; overexpression; participant enrollment; patient derived xenograft model; predicting response; predictive marker; response; response biomarker; restoration; safety assessment; standard of care; synergism; therapy development; treatment response; tumor; tumor DNA

ABSTRACT – PROJECT 2 PARP inhibitors have emerged as an established standard of care option in epithelial ovarian cancer (OvCa). Approximately half of OvCa patients harbor inactivating genetic alterations in the homologous recombination (HR) pathway, which results in synthetic lethality with PARP inhibition (PARPi). PARPi have promising activity in HR-deficient OvCa. Even though less effective compared to HR-deficient OvCa, PARPis have also been shown to be active in HR-proficient OvCa. Unfortunately, the activity of PARPi is limited by the emergence of PARPi resistance. Therefore, there is an urgent need to identify potential strategies to reverse PARPi resistance in OvCa. Our preliminary studies suggest that inhibition of BRD4 activity by bromodomain extraterminal inhibitors (BETi) is an attractive approach to reverse PARPi resistance. Notably, the BRD4 genomic locus 19p13.12 is often amplified in high-grade serous OvCa (~20%). Indeed, BRD4 amplification/overexpression correlates with a poor prognosis in these patients. We and others have shown that BETis play a major role in suppressing the HR pathway and impairing the G2/M checkpoint, which reverses resistance to PARPi caused by restoration of the HR pathway. Therefore, our central hypothesis is that targeting BRD4 activity using clinically applicable BET inhibitor is sufficient to overcome resistance to PARPi developed in recurrent OvCa. We also hypothesize that targeting BRD4 will sensitize tumor to PARPi by simultaneously downregulating HR activity, specifically BRCA1, RAD51 and TOPBP1 expression, and impairing the G2/M phase of the cell cycle by suppressing WEE1 activity, leading to DNA damage accumulation and mitotic catastrophe. Accordingly, the objective of the present study is to evaluate the safety and efficacy of a combination of PARPi and BETi in recurrent PARPi-resistant platinum-sensitive OvCa. We also plan to assess the impact of PARPi-BETi combination on functional HR activity and percent reduction compared to baseline and correlate with objective response to therapy. Further, we plan to investigate the mechanistic basis of these findings in patient-derived models obtained from the patients enrolled in the trial. To achieve that, we propose the following specific aims (SA): SA1. To determine the safety and efficacy of PARPi combined with BETi in patients with recurrent PARPi-resistant OvCa in a phase Ib clinical trial. SA2. To investigate the impact of the combined regimen on modulating HR and DNA damage response (DDR) pathways as well as G2-M cell cycle checkpoint using tissue and circulating tumor DNA samples both at baseline, on treatment and at time of progression. SA3: To investigate the mechanisms of response and resistance to the combination regimen in preclinical models. The potential impact is significant as there is an urgent need to overcome resistance to PARPi in OvCa. This project investigates a novel new therapeutic direction combining PARPi with epigenetic therapy by BETi. PARPi resistance is a major challenge given that PARPi are now approved in first line and recurrent settings. Further, this study will investigate predictive biomarkers, which will help identify patients who benefit from this regimen. Successful execution of this study will provide a rationale to advance this regimen into scientifically rationalized trials focused on improving the outcome of this most lethal cancer with limited treatment options.

摘要 - 项目2 PARP抑制剂已成为上皮卵巢癌（OVCA）的既定护理选择。 大约一半的OVCA患者在同源重组中灭活遗传改变 （HR）途径，导致pARP抑制（PARPI）的合成致死性。 PARPI有希望的活动 在HR缺乏的OVCA中。即使与缺乏人力资源的OVCA相比，帕尔皮斯也效果不佳 证明在富于HR的OVCA中活跃。不幸的是，PARPI的活动受到了出现的限制 parpi抗性。因此，迫切需要确定潜在的策略来逆转PARPI抵抗 在OVCA。我们的初步研究表明，溴结构域外部抑制剂对BRD4活性的抑制作用 （beti）是一种逆向parpi抗性的有吸引力的方法。值得注意的是，BRD4基因组基因座19p13.12是 通常在高级浆液OVCA（约20％）中放大。确实，BRD4扩增/过表达与 这些患者的预后不佳。 我们和其他人表明，贝蒂斯在抑制人力资源途径和损害G2/m方面发挥了重要作用 检查点，它逆转了由人力资源途径恢复引起的对PARPI的阻力。因此，我们的 中心假设是，使用临床上适用的BET抑制剂靶向BRD4活性就足够了 为了克服对复发性ovca中parpi的抗性。我们还假设针对BRD4 通过简单地下调HR活性，特别是BRCA1，RAD51和 TOPBP1表达，并通过抑制WEE1活性来损害细胞周期的G2/M期，导致 DNA损伤积累和有丝分裂灾难。根据本研究的目的是 评估PARPI和BETI在反复抗性中的安全性和效率 铂敏感的OVCA。我们还计划评估Parpi-Beti组合对功能HR的影响 与基线相比，活动和降低百分比与对治疗的客观反应相关。此外， 我们计划在从患者衍生的模型中研究这些发现的机械基础 参加试验的患者。为此，我们提出以下特定目标（SA）：SA1。确定 parpi的安全性和易感性与BETI在一个阶段复发性抗性OVCA的患者相结合 IB临床试验。 SA2。研究合并方案对调节HR和DNA损伤的影响 使用组织和循环肿瘤DNA样品的响应（DDR）途径以及G2-M细胞周期检查点 在基线，治疗和进展时。 SA3：调查响应机制和 临床前模型中对组合方案的抗性。潜在影响很大，因为有一个 迫切需要克服OVCA对PARPI的抵抗。该项目调查了一种新的新疗法 通过BETI结合PARPI和表观遗传疗法的方向。鉴于 PARPI现在以第一行和经常性设置获得批准。此外，这项研究将研究预测 生物标志物将有助于确定从该方案中受益的患者。成功执行这项研究 将提供一个理由，将该方案推进科学合理化的试验，重点是改善 这种最致命的癌症的结果具有有限的治疗选择。