Targeting DNA Repair in Selected Patients with Pancreatic Cancer: An Approach to

改善胰腺癌患者治疗的尝试在很大程度上未能取得有意义的效果。 提高生存率。因此，迫切需要鉴定特定的分子变化， 定义预后并指导治疗决策。BRCA 1和BRCA 2癌症易感性中的突变 与DNA双链同源重组修复（HRR）缺陷相关的基因 断裂是这种预测和预后生物标志物的主要实例。BRCA 1和BRCA 2 突变与对PARP抑制剂的超敏反应有关，这会加重DNA的形成， HRR缺陷细胞中的双链断裂。虽然BRCA 1、BRCA 2、PALB 2和ATM的突变是 与5%至8%的胰腺癌患者相关，其他基因的改变也会导致胰腺癌的发生。 对PARP抑制剂敏感，可能存在于15%至20%的胰腺肿瘤中。我们假设 PARP抑制剂治疗将提高胰腺癌患者的生存率， HRR机器的缺陷。我们建议研究rucaparib（CO-338）对HRR的影响 基于临床前研究显示rucaparib对BRCA 2具有细胞毒性， 与其他PARP抑制剂相比，PARP抑制剂对HRR缺陷型胰腺癌细胞的作用更大。 在目的1中，我们将描述HRR活性介质对PARP抑制剂反应的影响， 胰腺癌特别是，我们将评估癌症易感基因和体细胞基因缺陷是否 与HRR缺陷有关的基因的改变影响胰腺癌细胞中rucaparib的反应。在 目的2：研究DNA不稳定性和基于基因表达的模型识别DNA的能力 损伤反应缺陷肿瘤，以预测胰腺肿瘤对化疗的反应。在目标3中， 将进行rucaparib在化疗难治性HRR缺陷胰腺癌中的II期研究。我们 将通过使用快速筛查HRR相关基因缺陷的患者来选择参与者， 通量DNA修复基因测序测试。来自II期的体外细胞系模型和患者材料 试验将用于探索rucaparib的耐药机制。

Attempts to improve therapy for pancreatic adenocarcinoma patients have largely failed to meaningfully improve survival. Therefore, there is a critical need for identification of specific molecular changes that define prognosis and guide therapy decisions. Mutations in the BRCA1 and BRCA2 cancer susceptibility genes, which are associated with defects in homologous recombination repair (HRR) of DNA double strand breaks, are prime examples of such predictive and prognostic biomarkers. Specifically, BRCA1 and BRCA2 mutations are associated with hypersensitivity to PARP inhibitors, which accentuate the formation of DNA double strand breaks in HRR deficient cells. While mutations in BRCA1, BRCA2, PALB2 and ATM are associated with 5% to 8% of pancreatic cancer patients, alterations in other genes that also confer sensitivity to PARP inhibitors, may be present in 15% to 20% of pancreatic tumors. We hypothesize that PARP inhibitor therapy will improve survival for pancreatic cancer patients, when patients are selected for defects in the HRR machinery. We propose to investigate the impact of rucaparib (CO-338) on HRR deficient pancreatic cancer cells based on preclinical studies showing that rucaparib is cytotoxic to BRCA2 deficient cells and has greater effects on HRR deficient pancreatic cancer cells than other PARP inhibitors. In Aim 1 we will characterize the influence of mediators of HRR activity on response to PARP inhibitors in pancreatic cancer. In particular, we will assess whether defects in cancer susceptibility genes and somatic alterations in genes implicated in HRR deficiency influence rucaparib response in pancreatic cancer cells. In Aim 2 we will investigate the ability of DNA instability and gene expression-based models, that identify DNA damage response deficient tumors, to predict response to chemotherapy in pancreatic tumors. In Aim 3 we will conduct a Phase II study of rucaparib in chemotherapy refractory HRR deficient pancreatic cancer. We will select participants by rapidly screening patients for defects in HRR associated genes using a rapid throughput DNA repair gene sequencing test. In vitro cell line models and patient materials from the phase II trial will then be used to explore mechanisms of resistance to rucaparib.