"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.

项目二项目总结