"Optimizing synthetic lethality in high-grade serous ovarian cancer"

项目2项目总结 卵巢高级别浆液性癌(HGSC)是最致命的妇科恶性肿瘤。超过80%的 HGSC患者在标准化疗后复发。我们已经鉴定出一种新的高活性的基因毒素 共同抑制多聚ADP核糖聚合酶(PARP)和ATR检查点激酶的治疗。组合PARP ATR抑制(PARPI-ATRI)协同特异性靶向和杀伤卵巢HGSCs 常见的HGSC相关改变，例如同源重组(HR)缺陷和Cyclin E 过度表达。我们的初步研究表明，PARPI-ATRI联合使用在杀灭 具有这些改变的肿瘤细胞甚至导致HR缺陷和Cyclin E过表达的消退 卵巢HGSCs。在临床上，单独对卵巢癌进行PARP抑制(PARPI)治疗会导致部分 肿瘤消退，很少完全缓解，最终出现耐药。这项建议 通过使用一种有效的新组合疗法来转换部分反应，满足了这一紧迫的临床需求 随着PARPI的单一治疗，肿瘤完全持久地消退。 对于这些研究，我们开发了：1)&gt；60个PDX模型，代表了临床上最常见和 具有挑战性的治疗条件包括：HR缺乏、PARPI耐药和Cyclin E过表达 具有不同铂敏感性的HGSC，2)一种新型的PARPI示踪剂，将作为一种预测和 指导PARPI治疗患者选择的药效学标记物，3)先进的蛋白质组学方法 检测全球肿瘤和复制分叉对治疗的特异性反应。我们假设双重抑制 与卵巢癌相比，PARP和ATR的表达将增加卵巢癌肿瘤完全消退的频率 PARPI单一疗法。在此建议的研究将测试PAPR抑制剂(PARPI，olaparib)的有效性，通过 联合ATR抑制剂(ATRI，AZD-6738)治疗卵巢癌的首个临床试验 临床前数据。其次，我们将确定剂量计划策略，以最大限度地减少药物毒性，而不是 PARPI-ATRI在PDX模型中的折衷效果。联合使用PARPI-ATRI已显示出疗效和 早期IB试验的耐受性，但降低毒性的方法对于优化这些患者的生活质量很重要 病人。最后，我们将进行基因组和蛋白质组研究，以确定PARPI-ATRI反应的生物标记物 在未来的临床试验中进行评估。我们的霍普金斯-宾夕法尼亚大学孢子团队包括：临床试验专家， 拥有临床前模型和药物优化专业知识的转化型科学家，拥有 在DNA复制压力、孢子芯等病理学方面的专业知识将促进最佳患者组织 采购和处理以及生物统计，以监督数据分析。因此，我们的团队为成功做好了准备 实现项目2的目标。

PROJECT 2 PROJECT SUMMARY Ovarian high-grade serous cancer (HGSC) is the most lethal gynecological malignancy. More than 80% of HGSC patients recur after standard chemotherapy. We have identified a novel and highly active genotoxic therapy by co-inhibiting poly-ADP ribose polymerase (PARP) and ATR checkpoint kinase. Combination PARP inhibition with ATR inhibition (PARPi-ATRi) synergizes to specifically target and kill ovarian HGSCs harboring common HGSC-associated alterations, e.g. homologous recombination (HR) deficiency and Cyclin E overexpression. Our preliminary studies show that PARPi-ATRi in combination is especially effective in killing tumor cells with these alterations and even causing regression of HR-deficient and Cyclin E overexpressing ovarian HGSCs. In the clinic, PARP inhibition (PARPi) treatment alone for ovarian cancer alone results in partial tumor regression and rarely complete responses with the ultimate emergence of drug resistance. This proposal addresses this urgent clinical need by using a potent new combination treatment to convert partial responses with PARPi monotherapy into complete and durable tumor regression. For these studies, we have developed: 1) >60 PDX models representing the clinically most common and challenging conditions to treat including: HR-deficient, PARPi-resistant and Cyclin E overexpressing ovarian HGSCs with differing platinum sensitivities, 2) a novel PARPi tracer that will be tested as a predictive and pharmacodynamic marker to guide patient selection for PARPi therapies, 3) advanced proteomic methods to detect both global-tumor and replication fork-specific responses to treatment. We hypothesize that dual inhibition of PARP and ATR will increase the frequency of complete tumor regression in ovarian cancer compared to PARPi monotherapy. The proposed studies herein will test the efficacy of PAPR inhibitor (PARPi, olaparib), by combination with ATR inhibitor (ATRi, AZD-6738) in the first clinical trial in ovarian cancer supported by our preclinical data. Secondly, we will identify dosing schedule strategies to minimize drug toxicity without compromising efficacy for PARPi-ATRi in PDX models. Combination PARPi-ATRi has shown efficacy and tolerability in early phase IB trials, but ways to decrease toxicity are important to optimize quality of life for these patients. Finally, we will perform genomic and proteomic studies to identify biomarkers of PARPi-ATRi response for evaluation in future clinical trials. Our Hopkins–PENN SPORE team is comprised of: expert clinical trialists, translational scientists with preclinical models and drug optimization expertise, molecular biologists with expertise in DNA replication stress, SPORE Cores such as Pathology that will promote optimal patient tissue procurement and processing and Biostats to oversee data analysis. Thus, our team is well positioned for success with realizing Project 2 goals.