Pre-Clinical Evaluation of Novel Therapeutics for PDA

描述（由申请人提供）：胰腺导管腺癌（PDA）是一种独特的致命疾病，目前尚无治愈方法。目前的药物治疗方案只能延长患者数周的生存时间，甚至手术切除“可切除”的PDA也不能防止疾病复发。由于缺乏真正可预测的临床前筛查工具，这种或任何癌症的新药的发现受到阻碍。基因工程的最新进展已经允许创建复杂的小鼠模型，这些模型概括了人类癌症的基因型和表型特征。我建议使用最近描述的PDA小鼠模型来评估几种药物导致已建立的PDA逆转的能力。该模型基于K-ras和p53的条件突变，这两种基因是胰腺癌中最常见的突变基因。对肿瘤发生的影响将通过目前正在研究的几种成像方式进行追踪。为了验证这一模型，PDA小鼠将首先使用先前在人类患者身上测试过的药物进行治疗。在此之后，针对相关途径的新型药物将在高通量环境中进行评估。

DESCRIPTION (provided by applicant): Pancreatic Ductal Adenocarcinoma (PDA) is a uniquely lethal disease for which there is no cure. Current drug regimens prolong survival by just weeks and even surgical removal of 'resectable' PDA fails to prevent disease recurrence. The discovery of new drugs for this or any cancer is hindered by a lack of truly predictive preclinical screening tools. Recent advances in genetic engineering have allowed the creation of sophisticated mouse models that recapitulate both the genotypic and phenotypic hallmarks of human cancers. I propose to use a recently-described mouse model of PDA to evaluate the ability of several agents to cause reversion of established PDAs. This model is based on the conditional mutation of K-ras and p53, two of the most frequently mutated genes in pancreatic cancer. Effects on tumorigenesis will be tracked via several imaging modalities currently under investigation. In order to validate this model, the PDA mice will initially be treated with drugs previously tested in human patients. Following this, novel agents targeting relevant pathways will be evaluated in a high-throughput setting.