SPORE in Pancreatic Cancer

描述（由申请人提供）：本申请的胰腺癌研究卓越专业项目侧重于解决对改善胰腺癌患者预后具有重要意义的基础和临床问题的转化研究。具体而言，本项目的研究项目旨在：1)开发和测试早期和晚期胰腺癌患者的新治疗策略，包括化疗和放化疗；2)结合临床试验开展基础研究，从分子水平上深入了解药物成功和失败的原因

DESCRIPTION (provided by applicant): This application for a Specialized Program of Research Excellence in Pancreatic Cancer focuses on translational studies that address basic and clinical issues of importance to improving the outcome of patients with pancreatic cancer. Specifically, the research projects in this program seek to: 1) develop and test novel therapeutic strategies including chemotherapy, and chemoradiation therapy for patients with early and advanced pancreatic cancer; 2) undertake basic research studies in conjunction with clinical trials that will provide insight at the molecular level into the reasons for success and failure of the different strategies. The first project investigates potential of novel inhibitors of CDKS to block tumor progression and nociceptive signaling (pain) in preclinical animal models and in a phase I clinical trial in patients that have failed other therapies. The second project investigate further the molecular nature of radioresistance in patients with borderline resectable disease and proposes a clinical trial with inhibitors of the cholesterol synthesis pathway (Zometa) as a therapeutic intervention. The third project investigates therapeutic strategies that may be effective in SMAD4 mutant and SMAD4 wildtype tumors and proposes a novel clinical trial with a combination of an HDAC inhibitor (Belinostat) and an inhibitor to surviving (YM155) in patients that have failed other therapies. The fourth project investigates the possibility that a hypoxic an desmoplastic environment in pancreatic cancer affects metabolic features of the tumor and stroma that result in high endogenous production of cytidine, which in turn causes drug resistance to fluropyrimidines. Two therapeutic strategies that inhibit hypoxia (digoxin) and pyrimidine biosynthesis (leflunomide) will be investigated in a clinical trial, and the possibility that cytidine and associated metabolites can serve as biomarkers of drug resistance will be investigated. Our tissue core proposes to continue its unique collection of metastatic tumor samples through our rapid autopsy program, in addition to capturing samples associated with surgical resections. All projects are supported by administrative and biostatistics cores.