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

“优化高级别浆液性卵巢癌的综合致死率”

• 批准号: 10478846
• 负责人: FIONA SIMPKINS
• 金额: $ 30.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478846
• 关键词: ATR gene; Address; Back; Binding; Biological Markers; CCNE1 gene; Cancer Patient; Carcinoma; Cell Cycle Regulation; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; DNA Double Strand Break; DNA Repair Gene; DNA biosynthesis; DNA replication fork; Data; Data Analyses; Defect; Dependence; Dose; Double Strand Break Repair; Drug resistance; Drug toxicity; Evaluation; Frequencies; Future; Genes; Genomics; Goals; Human; Imaging Device; In complete remission; Lead; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Molecular; Molecular Profiling; Ovarian; PET/CT scan; Pathology; Patient Selection; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase Ib Trial; Phosphotransferases; Platinum; Poly(ADP-ribose) Polymerases; Positioning Attribute; Positron-Emission Tomography; Pre-Clinical Model; Proteomics; Quality of life; Recurrence; Resistance; Resolution; Sampling; Schedule; Serous; TP53 gene; Testing; Tissue Procurements; Toxic effect; Tracer; Translating; base; brca gene; cancer biomarkers; cancer cell; cancer therapy; chemotherapy; drug response prediction; efficacy evaluation; efficacy testing; experimental study; genotoxicity; homologous recombination; improved; inhibitor; inhibitor therapy; neoplastic cell; novel; overexpression; partial response; patient derived xenograft model; pharmacodynamic biomarker; pre-clinical; predicting response; predictive marker; replication stress; response; response biomarker; success; tissue processing; translational scientist; treatment effect; treatment response; tumor

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.

项目 2 项目概要 卵巢高级别浆液性癌（HGSC）是致死率最高的妇科恶性肿瘤，占80%以上。 HGSC 患者在标准化疗后复发。我们已经鉴定出一种新型的高活性基因毒性物质。 通过共同抑制聚 ADP 核糖聚合酶 (PARP) 和 ATR 检查点激酶组合进行治疗。 抑制与 ATR 抑制 (PARPi-ATRi) 协同作用，特异性靶向并杀死含有卵巢 HGSC 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 我们的初步研究表明，PARPi-ATRi 组合在杀灭细胞方面特别有效。 肿瘤细胞发生这些改变，甚至导致 HR 缺陷和 Cyclin E 过表达的消退 在临床上，单独使用 PARP 抑制 (PARPi) 治疗卵巢癌会导致部分卵巢癌。 肿瘤消退并且很少完全缓解，最终出现耐药性。 通过使用有效的新联合治疗来转化部分反应来解决这一紧迫的临床需求 通过 PARPi 单一疗法实现肿瘤完全且持久的消退。 对于这些研究，我们开发了：1) > 60 个 PDX 模型，代表了临床上最常见和最常见的 PDX 模型。 需要治疗的挑战性病症包括：HR 缺陷、PARPi 耐药和 Cyclin E 过度表达的卵巢 具有不同铂敏感性的 HGSC，2) 一种新型 PARPi 示踪剂，将作为预测和测试进行测试 药效学标志物指导患者选择 PARPi 疗法，3) 先进的蛋白质组学方法 检测对治疗的整体肿瘤和复制叉特异性反应。 与相比，PARP 和 ATR 会增加卵巢癌肿瘤完全消退的频率 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。 在我们支持的第一个卵巢癌临床试验中与 ATR 抑制剂（ATRi，AZD-6738）联合使用 临床前数据。其次，我们将确定给药方案策略，以最大限度地减少药物毒性，而无需 PARPi-ATRi 组合在 PDX 模型中已显示出功效和效果。 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很重要 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。 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，具有 DNA 复制压力、SPORE 核心（例如病理学）方面的专业知识将促进最佳的患者组织 采购和处理以及 Biostats 来监督数据分析，因此，我们的团队已经做好了成功的准备。 实现项目 2 的目标。