"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项目摘要 卵巢高级浆液癌（HGSC）是最致命的妇科恶性肿瘤。超过80％ HGSC患者在标准化疗后复发。我们已经确定了一种新颖且高度活跃的遗传毒素 通过共抑制聚ADP核糖聚合酶（PARP）和ATR检查点激酶的治疗。组合parp 用ATR抑制（PARPI-ATRI）协同抑制，以专门针对和杀死携带的卵巢HGSC 常见的HGSC相关改变，例如同源重组（HR）缺乏和细胞周期蛋白E 过表达。我们的初步研究表明，结合parpi-atri在杀死中特别有效 具有这些改变的肿瘤细胞，甚至导致HR缺乏和细胞周期蛋白E过表达的消退 卵巢HGSC。在诊所中，仅针对卵巢癌的PARP抑制（PARPI）治疗会导致部分 肿瘤的回归和很少与耐药性最终出现的完全反应。这个建议 通过使用潜在的新组合治疗转换部分反应来解决这种紧急临床需求 将PARPI单一疗法成完全耐用的肿瘤回归。 对于这些研究，我们已经开发了：1）> 60 PDX模型代表了临床上最常见的 治疗的挑战性条件包括：HR缺陷，耐parpi和cyclin E过表达卵巢 具有区分铂灵敏度的HGSC，2）一种新型的Parpi示踪剂，将被视为预测和 指导患者选择PARPI疗法的药房标记，3）先进的蛋白质组学方法 检测全球肿瘤和复制叉特异性对治疗的反应。我们假设双重抑制 与PARP和ATR相比，PARP和ATR将增加卵巢癌的完全肿瘤消退的频率 PARPI单一疗法。本文提出的研究将测试PAPR抑制剂（Parpi，Olaparib）的效率， 在我们支持的卵巢癌中，与ATR抑制剂（ATRI，AZD-6738）结合使用了我们 临床前数据。其次，我们将确定给药计划策略，以最大程度地减少药物毒性 PDX模型中Parpi-Atri的损害效率。组合parpi-atri表现出效率和 早期IB试验的耐受性，但是降低毒性的方法对于优化这些生活质量很重要 患者。最后，我们将进行基因组和蛋白质组学研究以鉴定parpi-atri反应的生物标志物 在以后的临床试验中进行评估。我们的霍普金斯 - 彭诺孢子团队已完成：专家临床试验， 具有临床前模型和药物优化专业知识的转化科学家，分子生物学家 在DNA复制应力方面的专业知识，孢子核心（例如病理），这些核心将促进最佳患者组织 采购，加工和生物稳定器以监督数据分析。那，我们的团队在成功方面处于良好状态 实现项目2个目标。