A Model for Preclinical Biomarker Discovery in Pancreatic Ductal Adenocarcinoma

描述（申请人提供）：胰腺导管腺癌（PDA）是一种致命的恶性肿瘤。早期的全身扩散和对化疗的耐药性使PDA成为现代医学中最令人沮丧的诊断之一。然而，目前有数百种实验性抗癌药物正在开发中，可以考虑用于治疗胰腺导管腺癌（PDA）。我们迄今为止的研究表明，PDA可以分为不同的亚类，这些亚类在生物学上不同，对治疗的反应也不同。我们现在的目标是通过完善胰腺导管腺癌（PDA）的分子描述符，确定Ras途径上对特定肿瘤有效的治疗药物，并最终在生物标志物引导的临床试验中对这些药物进行测试，从而推进PDA的治疗。这将通过两个目标的工作来实现。目的1将在一组具有良好特征的PDA细胞系中确定并模拟对Raf-MEK-ERK和PI3激酶/Akt通路抑制剂反应的组学决定因素。由于我们怀疑联合阻断将是必需的，我们计划测试这些药物单独和联合。目的2将验证从患者身上切除的一组PDA异种移植物细胞系中发现的敏感性和耐药性生物标志物，并在小鼠中进行繁殖和治疗。在两种临床前系统中识别特定反应的生物标志物将在生物标志物引导的Ras途径抑制剂临床试验中进行测试（超出了本提案的范围）。总的来说，我们希望验证在有效的临床前模型系统筛选中确定的生物标志物将在临床试验中前瞻性地识别药物反应和耐药患者的假设。如果这是真的，这将使目前正在开发的实验药物能够快速测试对PDA亚类的疗效，然后迅速进入最有可能有效的患者亚群的试验。这项工作与胰腺导管腺癌100%相关。

DESCRIPTION (provided by applicant): Pancreatic Ductal Adenocarcinoma (PDA) is a deadly malignancy. Early systemic spread and resistance to chemotherapy combine to make PDA one of the most dismal diagnoses in modern medicine. However, hundreds of experimental anticancer medicines are now in development and could be considered for Pancreatic Ductal Adenocarcinoma (PDA). Our studies to date show that PDA can be divided into distinct subclasses that differ biologically and that may respond differently to treatment. Our goal now is to advance treatment of PDA by refining molecular descriptors of Pancreatic Ductal Adenocarcinoma (PDA), identifying therapeutic agents on the Ras pathway that are effective in specific tumors, and eventually testing these in biomarker-marker guided clinical trials. This will be accomplished through work in two aims. Aim 1 will identify and model omic determinants of response to inhibitors of the Raf-MEK-ERK and PI3 Kinase/Akt pathways in a well characterized panel of PDA cell lines. Since we suspect that combined blockade will be required, we plan to test these agents both alone and in combination. Aim 2 will validate the biomarkers of sensitivity and resistance discovered in cell lines in a selected panel of PDA xenografts resected from patients and propagated and treated in the mouse. Biomarkers identifying specific responses in both preclinical systems will be tested in biomarker-guided clinical trials with inhibitors of the Ras pathway (beyond the scope of this proposal). Overall, we expect to test the hypothesis that biomarkers identified in efficient, preclinical model system screens will prospectively identify drug responsive and drug resistant patients in clinical trials. If true, this will allow experimental drugs now under development to be quickly tested for efficacy in subclasses of PDA and then moved quickly into trials in patient subpopulations in which they are most likely to be effective. This work is 100% relevant to Pancreatic Ductal Adenocarcinoma. PUBLIC HEALTH RELEVANCE: Clinical Trials in oncology often fail because the tested drugs do not work in patients. This project will employ molecular analysis of pancreatic tumors to predict which tumors and patients will be most sensitive to certain treatments. These studies hold promise in expanding treatment options for pancreatic cancer patients, and changing the way clinical trials are conducted.