SPORE in Pancreatic Cancer

描述（由申请人提供）：本申请的胰腺癌卓越研究专业计划侧重于转化研究，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。具体而言，该计划的研究项目旨在：1）开发和测试新的治疗策略，包括早期和晚期胰腺癌患者的化疗和放化疗; 2）进行基础研究与临床试验，在分子水平上深入了解治疗成功和失败的原因。 不同的战略。第一个项目研究了新型CDKS抑制剂在临床前动物模型和I期临床试验中阻断肿瘤进展和伤害性信号（疼痛）的潜力。第二个项目进一步研究了边缘可切除疾病患者的放射抗性的分子性质，并提出了一项临床试验，其中胆固醇合成途径抑制剂（Zometa）作为治疗干预。第三个项目研究了可能对SMAD 4突变型和SMAD 4野生型肿瘤有效的治疗策略，并提出了一项新的临床试验，在其他治疗失败的患者中联合使用HDAC抑制剂（Belinostat）和生存抑制剂（YM 155）。第四个项目研究胰腺癌中缺氧促纤维增生环境影响肿瘤和间质代谢特征的可能性，这些代谢特征导致高内源性胞苷产生，从而导致对氟嘧啶类药物的耐药性。将在临床试验中研究抑制缺氧（地高辛）和嘧啶生物合成（来氟米特）的两种治疗策略， 胞苷和相关代谢物可以作为耐药性的生物标志物将被研究。我们的组织核心建议通过我们的快速尸检计划继续其独特的转移性肿瘤样本的收集，除了捕获与手术切除相关的样本。所有项目都得到行政和生物统计核心的支持。

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.