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

改善胰腺癌患者治疗方法的尝试在很大程度上失败了 提高存活率。因此，迫切需要确定特定的分子变化， 确定预后并指导治疗决定。BRCA1和BRCA2癌症易感性的突变 与DNA双链同源重组修复缺陷相关的基因 突变，是这种预测和预后生物标记物的主要例子。具体地，BRCA1和BRCA2 突变与对PARP抑制剂的超敏有关，PARP抑制剂会加剧DNA的形成 HRR缺陷细胞的双链断裂。而BRCA1、BRCA2、PALB2和ATM的突变是 与5%至8%的胰腺癌患者相关，其他基因的变化也与 对PARP抑制剂的敏感性，可能存在于15%到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存活率 HRR机制中的缺陷。我们建议研究Rucaparib(CO-338)对HRR的影响 基于临床前研究表明Rucaparib对BRCA2具有细胞毒性的缺陷胰腺癌细胞 与其他PARP抑制剂相比，它对HRR缺陷的胰腺癌细胞有更大的作用。 在目标1中，我们将表征HRR活性的介体对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躯体的缺陷 HRR缺陷相关基因的改变影响胰腺癌细胞对Rucaparib的反应。在……里面 目的2我们将研究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》中我们 将进行Rucaparib治疗化疗难治性HRR缺陷型胰腺癌的II期研究。我们 将通过使用快速筛查技术快速筛查患者HRR相关基因缺陷来选择参与者 DNA修复基因全量测序试验。体外细胞系模型和II期患者材料 然后将利用试验来探索鲁卡帕利的耐药机制。

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.