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

描述（由申请人提供）：胰腺导管腺癌是美国癌症死亡的第四大原因，并且在任何实体癌中生存率最低。个性化癌症治疗的目标是识别预测药物反应的分子缺陷，或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，这表明需要个性化的癌症治疗。为此，我们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基因大多数是在同源DNA修复中，包括BRCA 2/BRCA 1/PALB 2/Fanconi贫血通路突变。具有同源DNA修复缺陷的胰腺癌和其他癌症对Parp抑制剂和其他导致双链DNA断裂的药物非常敏感。Parp抑制剂奥拉帕尼（olaparib）目前处于2期临床试验阶段，在卵巢癌患者中显示出44%的反应率。因此，我们提出了一项临床试验，将患者随机分配至低剂量DNA链断裂方案，每月一次化疗（伊立替康、顺铂、博来霉素和丝裂霉素C），联合或不联合口服Parp抑制剂奥拉帕尼。我们将针对最有可能对本方案产生应答的患者，包括已知BRCA突变、家族性胰腺癌或德系犹太人血统的患者以及普通胰腺癌患者。患者及其癌症样本将接受基因检测，以鉴定同源DNA修复中的基因缺陷，以确定基因检测是否可以鉴定最有可能对基于Parp抑制剂的治疗有反应的患者。将从患者样本中开发细胞系，以将治疗的临床反应与实验室反应相关联。将测量循环突变体DNA，以确定其预测治疗反应的程度。 公共卫生相关性：胰腺癌是最致命的常见癌症，也是第四大常见癌症死亡原因。这种疾病需要使用个性化癌症治疗的临床试验。我们提出了一项随机2期试验，使用一种非常有前途的治疗方法，口服Parp抑制剂olarparib，联合治疗胰腺癌患者，根据他们的遗传特征和对这些药物的体外反应预测对这些药物有反应。

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.