A novel more effective genotoxic therapy for ovarian cancer

一种新的更有效的卵巢癌基因毒性疗法

基本信息

批准号：
10343698
负责人：
FIONA SIMPKINS
金额：
$ 36.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343698
关键词：
ATR gene Address Behavior Bioinformatics CCNE1 gene CRISPR/Cas technology Cancer Patient Candidate Disease Gene Cell Cycle Checkpoint Cessation of life Characteristics Chemoresistance Clinic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy DNA Double Strand Break DNA replication fork DNA sequencing Data Defect Dependence Double Strand Break Repair Drug resistance Frequencies Future Gene Proteins Genes Genetic Genome Stability Genomics Human In Vitro Lead Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Modeling Monitor Mus Mutation Patients Phosphotransferases Platinum Poly(ADP-ribose) Polymerases Positioning Attribute Primary Neoplasm Proteins Proteomics Recurrence Relapse Reporting Resistance Role Sampling Serous TP53 gene Testing Therapeutic Tumor Suppression Validation base brca gene cancer cell cancer genetics cancer therapy combinatorial effectiveness testing efficacy testing experimental study genotoxicity homologous recombination improved inhibitor inhibitor therapy innovation insight knock-down novel novel therapeutics overexpression patient derived xenograft model patient population patient stratification pre-clinical preclinical trial predictive marker prevent resistance mechanism response response biomarker targeted treatment transcriptome transcriptome sequencing transgene expression treatment optimization treatment strategy tumor

项目摘要

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. More than 80% of HGSOC patients recur after frontline standard therapy, and complete and durable responses are rare. Therapies that improve compete tumor regression and prevent relapse are needed. Our GOALS are to i) identify which ovarian cancer genetic subsets will benefit from a new more effective genetically targeted therapy using primary tumor cultures, patient-derived xenograft models and human tumor samples from our clinical trial, ii) identify mechanisms of acquired resistance with genetic validation. 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 HGSOCs harboring common HGSOC-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 HGSOC cells with these alterations and causes regression of HR-deficient and Cyclin E overexpressing HGSOC patient-derived xenografts (PDXs).These results have stimulated a clinical trial of PARPi-ATRi combination in recurrent HGSOC (unselected patient population) to be led by the PI of this proposal. This will be the first trial evaluating PAPRi-ATRi combination in ovarian cancer. Here, we propose to validate in vitro findings and expand the use of our PDX model, a reliable HGSOC surrogate, to test the effectiveness of this novel PARPi-ATRi combination in killing HGSOCs that either overexpress Cyclin E-or have acquired PARPi-resistance, which together cause most deaths from HGSOC. Our clinical trial of PARPi-ATRi for treatment of recurrent HGSOC will be performed in parallel with the expanded preclinical mouse studies. This will allow us to correlate predictive biomarkers (HR-deficiency and Cyclin E overexpression) of response and potential resistance mechanisms (e.g., BRCA reversion mutations). This PARPi-ATRi combination therapy is promising; however, this treatment causes tumor regression initially in chemo-resistant Cyclin E-overexpressing tumors but acquired resistance ultimately develops. Using genomic and proteomics, we will integrate alterations discovered in the PAPRi-ATRi-resistant and sensitive PDXs with patient samples from the clinical trial to develop a candidate pool list. Candidate genes associated with resistance will be refined by prioritizing alterations found at both the gene and protein level and that are druggable. The top candidates will be validated in vitro using a targeted CRISPR knock-down approach. Defining markers of response and resistance will help stratify patient populations, optimize treatment strategies and identify new targets for future therapeutics based on HGSOC cancer genetics.

高级浆液卵巢癌（HGSOC）是最致命的妇科恶性肿瘤。超过80％前线标准疗法后的HGSOC患者复发，并且完全耐用的反应很少。需要改善竞争肿瘤回归并预防复发的疗法。我们的目标是我）确定哪些卵巢癌遗传子集将受益于新的更有效的遗传靶向使用原发性肿瘤培养物，患者衍生的异种移植模型和人类肿瘤样品的治疗临床试验，ii）确定具有遗传验证的获得的抗性机制。我们通过共同抑制多ADP核糖确定了一种新型且高度活跃的遗传毒性疗法聚合酶（PARP）和ATR检查点激酶。组合PARP抑制与ATR抑制（parpi- Atri）协同靶向特定针对和杀死具有共同HGSOC相关的变化的HGSOC，例如同源重组（HR）缺陷和细胞周期蛋白E过表达。我们的初步研究表明结合组合的parpi-atri特别有效地杀死了HGSOC细胞，这些变化和原因 HR缺陷和细胞周期蛋白E过表达HGSOC患者衍生异种移植物（PDXS）的回归。结果刺激了复发性HGSOC中parpi-atri组合的临床试验（未选择患者人口）由该提案的PI领导。这将是评估帕普里atri组合的第一个试验卵巢癌。在这里，我们建议验证体外发现并扩展我们的PDX模型的使用，这是可靠的HGSOC 代理，测试这种新型Parpi-Atri组合在杀死HGSOC中的有效性过表达细胞周期蛋白E或获得了parpi抗性，这共同导致大多数HGSOC死亡。我们对复发性HGSOC治疗的parpi-atri的临床试验将与扩展的临床前小鼠研究。这将使我们能够关联预测性生物标志物（HR缺乏症和响应和潜在抗性机制（例如BRCA恢复突变）的过表达）。这种parpi-atri组合疗法是有希望的。但是，这种治疗会导致肿瘤消退最初是在化学耐药性细胞周期过表达的肿瘤中，但最终获得了耐药性。使用基因组和蛋白质组学，我们将整合在抗辣蛋白酶抗性和敏感的中发现的变化来自临床试验的患者样本的PDX可以开发候选池清单。相关的候选基因通过在基因和蛋白质水平上发现的变化的优先次数，将使用抗药性来完善可吸毒。顶级候选人将在体外使用目标CRISPR敲门方法在体外进行验证。定义反应和抵抗的标记将有助于分层患者人群，优化治疗策略并确定基于HGSOC癌症遗传学的未来治疗剂的新靶标。