SPORE in Pancreatic Cancer

描述(由申请者提供)：本申请为胰腺癌卓越研究专项计划，重点研究对改善胰腺癌患者预后至关重要的基础和临床问题的转化性研究。具体地说，该计划的研究项目寻求：1)为早期和晚期胰腺癌患者开发和测试新的治疗策略，包括化疗和化学放射治疗；2)结合临床试验进行基础研究，从分子水平深入了解胰腺癌成功和失败的原因。 不同的策略。第一个项目是在临床前动物模型和在其他治疗失败的患者的I期临床试验中，研究新型CDK抑制剂阻止肿瘤进展和伤害性信号(疼痛)的可能性。第二个项目进一步研究了交界性可切除疾病患者放射抵抗的分子本质，并提出了一项使用胆固醇合成途径抑制剂(Zometa)作为治疗干预的临床试验。第三个项目调查了可能对Smad4突变和Smad4野生型肿瘤有效的治疗策略，并提出了一项新的临床试验，将HDAC抑制剂(Belinostat)和存活抑制剂(YM155)结合在一起，用于治疗其他治疗失败的患者。第四个项目调查胰腺癌的低氧和促结缔组织生长环境影响肿瘤和间质的代谢特征，从而导致内源性胞苷的产生，进而导致对氟嘧啶的耐药性。两种抑制缺氧(地高辛)和嘧啶生物合成(来氟米特)的治疗策略将在临床试验中进行研究，其可能性 胞苷和相关代谢物是否可以作为耐药的生物标记物将进行调查。我们的组织核心计划通过我们的快速尸检计划继续其独特的转移性肿瘤样本收集，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.