Pre-Clinical Evaluation of Novel Therapeutics for PDA

描述(申请人提供)：胰腺导管腺癌(PDA)是一种独特的致命疾病，目前还没有治愈的方法。目前的药物治疗方案仅能将存活时间延长数周，即使手术切除“可切除的”PDA也无法防止疾病复发。由于缺乏真正具有预测性的临床前筛查工具，这种癌症或任何癌症的新药发现都受到阻碍。基因工程的最新进展使复杂的小鼠模型得以创建，这些模型概括了人类癌症的基因和表型特征。我建议使用最近描述的PDA的小鼠模型来评估几种代理导致已建立的PDA逆转的能力。这个模型是基于胰腺癌中最常见的两个突变基因K-ras和p53的条件性突变。对肿瘤形成的影响将通过目前正在研究的几种成像方式进行跟踪。为了验证这一模型，首先将用先前在人类患者身上测试的药物来治疗PDA小鼠。随后，针对相关通路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.