Predicting pancreatic cancer responses for a Parp inhibitor-based clinical trial

描述(申请人提供)：胰腺导管腺癌是美国癌症死亡的第四大原因，它是所有实体癌症中存活率最低的。个人化癌症治疗的目标是识别预测药物反应的分子缺陷，或者测试癌症本身的药物敏感性，并用最佳药物方案治疗患者。胰腺癌基因组计划确定了胰腺癌分子改变的异质性，表明个性化癌症治疗的必要性。为此，我们已经确定了胰腺癌化疗反应的分子预测因子。我们知道，家族性胰腺癌患者中突变的大多数基因都处于同源DNA修复中，包括BRCA2/BRCA1/PALB2/Fanconi贫血途径突变。胰腺癌和其他有同源DNA修复缺陷的癌症对PARP抑制剂和其他导致双链DNA断裂的药物非常敏感。PARP抑制剂奥拉帕利目前处于第二阶段临床试验，在卵巢癌患者中显示出44%的有效率。因此，我们提出了一项临床试验，患者随机接受每月一周期的低剂量DNA断链化疗(伊立替康、顺铂、博莱霉素和丝裂霉素C)，同时使用或不使用口服PARP抑制剂奥拉帕利布。我们将针对最有可能对该方案有反应的患者，包括已知的BRCA突变、家族性胰腺癌或德系胰腺癌患者以及普通胰腺癌患者。患者和他们的癌症样本将接受基因测试，以确定同源DNA修复中的基因缺陷，以确定基因测试是否可以确定最有可能对基于PARP抑制剂的治疗有反应的患者。将从患者样本中开发出细胞系，以将临床治疗反应与实验室反应联系起来。将对循环突变DNA进行测量，以确定其预测治疗反应的准确性。 公共卫生相关性：胰腺癌是常见癌症中最致命的，是癌症死亡的第四大常见原因。这种疾病需要利用个性化癌症治疗的临床试验。我们提出了一项随机的第二阶段试验，使用一种非常有前景的治疗方法，口服PARP抑制剂olarparib，结合治疗胰腺癌患者，根据他们的基因特征和对这些药物的体外反应，预计他们对这些药物有反应。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma is the 4th leading cause of cancer death in the United States and it has the lowest survival rate for any solid cancer. The goal of personalized cancer therapy is to identify molecular defects that predict drug responses or to test the cancers themselves for drug sensitivities and treat the patient with the optimal drug regimen. The pancreatic cancer genome project identified heterogeneity in the molecular alterations of pancreatic cancers indicating the need for personalized cancer therapy. To this end, we have identified molecular predictors of pancreatic cancer chemotherapy responses. We know that the majority of genes mutated in patients with familial pancreatic cancer are in the homologous DNA repair including BRCA2/BRCA1/PALB2/Fanconi Anemia pathway mutations. Pancreatic and other cancers with defects in homologous DNA repair are exquisitely sensitive to Parp inhibitors and to other drugs that cause double-strand DNA breaks. The Parp inhibitor, olaparib, now in phase 2 clinical trials, has shown a 44% response rate in patients with ovarian cancer. Therefore, we propose a clinical trial randomizing patients to a low-dose DNA strand break regimen of monthly cycles of chemotherapy (irinotecan, cisplatin, bleomycin and mitomycin C) with or without the oral Parp inhibitor, olarparib. We will target patients most likely to respond to this protocol including patients with known BRCA mutations, familial pancreatic cancer, or Ashkenazi ancestry as well as patients with usual pancreatic cancer. Patients and their cancer samples will undergo gene testing to identify gene defects in homologous DNA repair to determine if gene testing can identify patients most likely to respond to Parp inhibitor based therapy. Cell lines will be developed from patient samples to correlate clinical responses to therapy with responses in the laboratory. Circulating mutant DNA will be measured to determine how well it predicts response to therapy. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the deadliest of the common cancers and the 4th commonest cause of cancer death. Clinical trials that utilize personalized cancer therapy are needed for this disease. We propose a randomized phase 2 trial using a very promising therapy, the oral Parp inhibitor, olarparib, combined with therapies for patients with pancreatic cancer predicted to respond to these drugs based on their genetic profiles and in vitro responses to these agents.