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.

高级别浆液性卵巢癌（HGSOC）是最致命的妇科恶性肿瘤。超过80% 的 HGSOC 患者在一线标准治疗后复发，且完全且持久的缓解很少见。需要改善肿瘤完全消退并预防复发的疗法。我们的目标是 i) 确定哪些卵巢癌基因亚群将受益于新的更有效的基因靶向使用原代肿瘤培养物、患者来源的异种移植模型和来自我们的人类肿瘤样本进行治疗临床试验，ii) 通过基因验证确定获得性耐药机制。我们通过共同抑制聚 ADP 核糖确定了一种新型且高效的基因毒性疗法聚合酶 (PARP) 和 ATR 检查点激酶。 PARP 抑制与 ATR 抑制相结合（PARPi- ATRi）协同作用，专门针对并杀死具有常见 HGSOC 相关改变的 HGSOC，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 组合对于杀死具有这些改变和原因的 HGSOC 细胞特别有效 HR 缺陷和 Cyclin E 过表达 HGSOC 患者来源的异种移植物 (PDX) 的回归。这些结果刺激了 PARPi-ATRi 组合治疗复发性 HGSOC 的临床试验（未选择的患者人口）由本提案的 PI 领导。这将是第一个评估 PAPRi-ATRi 组合的试验卵巢癌。在这里，我们建议验证体外研究结果并扩大我们的 PDX 模型（一种可靠的 HGSOC）的使用替代物，以测试这种新型 PARPi-ATRi 组合在杀死 HGSOC 方面的有效性， Cyclin E 过度表达或获得 PARPi 抗性，这两者共同导致 HGSOC 的大多数死亡。我们的 PARPi-ATRi 用于治疗复发性 HGSOC 的临床试验将与扩大了临床前小鼠研究。这将使我们能够将预测生物标志物（HR 缺陷和细胞周期蛋白 E 过度表达）的反应和潜在的耐药机制（例如 BRCA 回复突变）。这种 PARPi-ATRi 联合疗法很有前景；然而，这种治疗会导致肿瘤消退最初出现在化疗耐药的 Cyclin E 过表达肿瘤中，但最终出现获得性耐药。使用基因组学和蛋白质组学，我们将整合在 PAPRi-ATRi 抗性和敏感性中发现的改变 PDX 使用临床试验中的患者样本来制定候选池列表。相关候选基因具有耐药性的将通过优先考虑在基因和蛋白质水平上发现的改变来完善，这些改变是可下药的。最优秀的候选者将使用靶向 CRISPR 敲低方法进行体外验证。定义反应和耐药标记将有助于对患者群体进行分层，优化治疗策略并根据 HGSOC 癌症遗传学确定未来治疗的新目标。