A Model for Preclinical Biomarker Discovery in Pancreatic Ductal Adenocarcinoma

描述（由申请人提供）：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联合收割机使PDA成为现代医学中最令人沮丧的诊断之一。然而，数百种实验性抗癌药物正在开发中，可以考虑用于胰腺导管腺癌（PDA）。我们迄今为止的研究表明，PDA可以分为不同的亚类，生物学上不同，可能会对治疗产生不同的反应。我们现在的目标是通过改进胰腺导管腺癌（PDA）的分子描述符来推进PDA的治疗，确定Ras通路上对特定肿瘤有效的治疗药物，并最终在生物标志物指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。目的1将在一组特征良好的PDA细胞系中鉴定和模拟Raf-MEK-ERK和PI 3激酶/Akt通路抑制剂应答的组学决定因素。由于我们怀疑需要联合封锁，我们计划单独和联合测试这些制剂。目的2将验证在从患者切除并在小鼠中繁殖和治疗的PDA异种移植物的选定组中的细胞系中发现的敏感性和抗性的生物标志物。在两种临床前系统中识别特异性反应的生物标志物将在生物标志物指导的Ras通路抑制剂临床试验中进行检测（超出本提案的范围）。总的来说，我们期望测试以下假设：在有效的临床前模型系统筛选中鉴定的生物标志物将在临床试验中前瞻性地鉴定药物应答和耐药患者。如果这是真的，这将使目前正在开发的实验性药物能够在PDA的亚类中快速测试疗效，然后快速进入最有可能有效的患者亚群的试验。这项工作是100%相关的胰腺导管腺癌。 公共卫生相关性：肿瘤学临床试验经常失败，因为测试的药物对患者不起作用。该项目将采用胰腺肿瘤的分子分析来预测哪些肿瘤和患者对某些治疗最敏感。这些研究有望扩大胰腺癌患者的治疗选择，并改变临床试验的进行方式。

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.