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

• 批准号: 10440098
• 负责人: FIONA SIMPKINS
• 金额: $ 39.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440098
• 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; 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) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Positioning Attribute; Primary Neoplasm; Proteins; Proteomics; Recurrence; Relapse; Reporting; Resistance; Role; Sampling; Serous; TP53 gene; Testing; Therapeutic; Tumor Promotion; Tumor Suppression; Validation; biomarker identification; brca gene; cancer cell; cancer genetics; cancer therapy; combinatorial; effectiveness testing; efficacy evaluation; efficacy testing; experimental study; genotoxicity; homologous recombination; improved; inhibitor; innovation; insight; knock-down; novel; novel therapeutics; overexpression; patient derived xenograft model; patient population; patient stratification; pre-clinical; preclinical trial; predictive marker; prevent; relapse prevention; resistance mechanism; response; response biomarker; synergism; targeted treatment; transcriptome; transcriptome sequencing; transgene expression; treatment optimization; treatment strategy; tumor

PROJECT SUMMARY 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.

项目摘要 高级别浆液性卵巢癌（HGSOC）是最致命的妇科恶性肿瘤。80%以上 HGSOC患者在一线标准治疗后复发，完全和持久的反应是罕见的。疗法 需要改善竞争性肿瘤消退和预防复发。我们的目标是：i）确定 卵巢癌基因亚型将受益于一种新的更有效的基因靶向治疗， 来自我们临床试验的肿瘤培养物、患者来源的异种移植物模型和人肿瘤样品，ii）鉴定 获得性抗性的机制与遗传验证。 我们已经确定了一种新的和高活性的基因毒性治疗，通过共抑制聚ADP核糖聚合酶 （PARP）和ATR检查点激酶。PARP抑制与ATR抑制的组合（PARPi-ATRi）协同作用 特异性靶向并杀死携带常见HGSOC相关改变的HGSOC，例如同源 重组（HR）缺陷和细胞周期蛋白E过表达。我们的初步研究表明，PARPi-ATRi在 组合在杀死具有这些改变的HGSOC细胞方面特别有效，并导致HR-1的消退。 缺乏和细胞周期蛋白E过表达的HGSOC患者来源的异种移植物（PDX）。这些结果刺激了 PARPi-ATRi联合治疗复发性HGSOC（HGSOC患者人群）的临床试验将由 该提案的PI。这将是第一项评估PAPRi-ATRi联合治疗卵巢癌的试验。 在这里，我们建议验证体外研究结果，并扩大使用我们的PDX模型，一个可靠的HGSOC 替代物，以测试这种新型PARPi-ATRi组合在杀死HGSOC中的有效性， 过度表达细胞周期蛋白E或获得PARPi抗性，这些共同导致HGSOC的大多数死亡。我们 PARPi-ATRi治疗复发性HGSOC的临床试验将与扩展的 临床前小鼠研究。这将使我们能够将预测性生物标志物（HR缺乏和细胞周期蛋白E） 过表达）的应答和潜在的抗性机制（例如，BRCA回复突变）。 这种PARPi-ATRi联合治疗是有希望的;然而，这种治疗最初会导致肿瘤消退。 在化疗耐药细胞周期蛋白E过度表达的肿瘤中，但最终会产生获得性耐药。使用基因组 和蛋白质组学，我们将整合在PAPRi-ATRi耐药和敏感PDX中发现的改变， 从临床试验中收集患者样本，以制定候选库列表。与抗性相关的候选基因 将通过优先考虑在基因和蛋白质水平上发现的可药用的改变来改进。顶部 候选物将使用靶向CRISPR敲低方法在体外进行验证。定义标志物 反应和耐药性将有助于对患者人群进行分层，优化治疗策略， 基于HGSOC癌症遗传学的未来治疗目标。