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抵抗使PDA成为现代医学中最令人沮丧的诊断之一。然而，数百种实验性的抗癌药物现在正在开发中，可以考虑用于治疗胰腺导管腺癌(PDA)。到目前为止，我们的研究表明，PDA可以分为不同的亚类，这些亚类在生物学上不同，对治疗的反应也可能不同。我们现在的目标是通过完善胰腺导管腺癌(PDA)的分子描述符来推进PDA的治疗，识别RAS途径上对特定肿瘤有效的治疗药物，并最终在生物标记物引导的临床试验中测试这些药物。这将通过两个目标的工作来实现。目标1将在一组特征良好的PDA细胞系中识别和模拟对Raf-MEK-ERK和PI3Kinase/Akt通路抑制剂的反应的组学决定因素。由于我们怀疑将需要联合封锁，我们计划单独和联合测试这些代理。目的2将验证在选定的从患者身上切除并在小鼠身上繁殖和治疗的PDA异种移植的细胞系中发现的敏感性和耐药性的生物标记物。识别两个临床前系统中特定反应的生物标记物将在生物标记物指导的临床试验中使用RAS途径的抑制剂进行测试(超出本提案的范围)。总体而言，我们希望测试这一假设，即在有效的临床前模型系统筛查中确定的生物标记物将在临床试验中前瞻性地识别药物敏感和耐药患者。如果这是真的，这将允许目前正在开发的实验药物在PDA亚类中快速测试有效性，然后迅速进入最有可能有效的患者亚群的试验。这项研究100%与胰腺导管腺癌相关。

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.