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

项目2项目概要 卵巢高级别浆液性癌（HGSC）是最致命的妇科恶性肿瘤。80%以上 HGSC患者在标准化疗后复发。我们发现了一种新型的高活性遗传毒性物质 通过共抑制聚ADP核糖聚合酶（PARP）和ATR检查点激酶进行治疗。组合PARP 抑制与ATR抑制（PARPi-ATRi）协同作用，特异性靶向并杀死携带 常见的HGSC相关改变，例如同源重组（HR）缺陷和细胞周期蛋白E 过度表达我们的初步研究表明，PARPi-ATRi组合在杀死 肿瘤细胞具有这些改变，甚至导致HR缺陷和Cyclin E过表达的消退 卵巢HGSC。在临床中，单独用于卵巢癌的PARP抑制（PARPi）治疗导致部分卵巢癌。 肿瘤消退，很少完全缓解，最终出现耐药性。这项建议 通过使用有效的新组合治疗来将部分反应转化为治疗， PARPi单药治疗的肿瘤完全和持久的消退。 对于这些研究，我们已经开发了：1）>60个PDX模型，代表临床上最常见的和最常见的肿瘤。 需要治疗的挑战性疾病包括：HR缺陷、PARPi耐药和细胞周期蛋白E过表达卵巢癌 具有不同铂敏感性的HGSC，2）一种新型PARPi示踪剂，将作为预测和 药效学标志物，以指导患者选择PARPi疗法，3）先进的蛋白质组学方法， 检测对治疗的全局肿瘤和复制叉特异性反应。我们假设双重抑制 PARP和ATR的联合应用将增加卵巢癌中肿瘤完全消退的频率， PARPi单药治疗。本文提出的研究将通过以下方式测试PAPR抑制剂（PARPi，奥拉帕尼）的功效： 联合ATR抑制剂（ATRi，AZD-6738）在卵巢癌的第一个临床试验中，由我们的 临床前数据。其次，我们将确定给药方案策略，以尽量减少药物毒性， 影响PARPi-ATRi在PDX模型中的功效。PARPi-ATRi组合已显示出功效， 早期IB试验中的耐受性，但降低毒性的方法对于优化这些患者的生活质量至关重要。 患者最后，我们将进行基因组和蛋白质组学研究，以确定PARPi-ATRi反应的生物标志物 用于未来临床试验的评估。我们的Hopkins-PENN SPORE团队由以下人员组成：临床试验专家， 具有临床前模型和药物优化专业知识的转化科学家， 在DNA复制应激、孢子核心（如病理学）方面的专业知识，将促进最佳患者组织 采购和处理以及Biostats监督数据分析。因此，我们的团队已做好成功的准备 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.