Antiangiogenic therapy of pancreatic cancer

描述(申请人提供)：胰腺癌是美国癌症死亡的第四大原因。不幸的是，这种疾病通常被诊断为晚期不治之症，只有不到5%的患者能存活5年。抗血管生成治疗在这种疾病中还没有得到很好的研究。这项研究的第一个具体目标将有助于确定血管生成抑制剂在胰腺癌小鼠模型中的作用，该模型与人类疾病非常相似。在具体目标1中，我将研究抗血管生成药物的不同组合。腺相关病毒将被用来运送新型抗血管生成药物。抗血管生成药物和化疗药物吉西他滨的组合也将进行测试。初步数据表明，在这个胰腺癌模型中，用重组TSP-1的I型重复序列(TSR)进行抗血管生成治疗时，细胞凋亡的重要性。因此，在特定的目标2中，我们将分析TSP-1参与介导细胞凋亡的信号转导通路的分子机制。完成这个有指导的项目将使我能够在新的传递机制方面获得深入的专业知识，例如基因治疗，重点是内皮细胞和肿瘤细胞对抗血管生成剂的反应的凋亡途径的详细分析。这一独特的组合将使我能够完成我职业发展的第一阶段，并向独立研究迈进。

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Unfortunately, this disease is often diagnosed at a late incurable stage, with less than 5% of patients surviving 5 years. Antiangiogenic therapy has not been well studied in this disease. The first specific aim of this study will help define the role of treatment with angiogenesis inhibitors in a mouse model of pancreatic cancer that closely resembles human disease. In specific aim 1 I will look at different combinations of antiangiogenic agents. Adenoassociated virus will be used to deliver novel antiangiogenic agents. Combinations of antiangiogenic agents and the chemotherapeutic agent, Gemcitabine, will also be tested. Preliminary data points to the importance of apoptosis during antiangiogenic therapy with recombinant Type I repeats of TSP-1 (TSR) in this model of pancreatic cancer. Therefore, in specific aim 2 the molecular mechanisms of the signal transduction pathways that are involved in mediating apoptosis by TSP-1 will be analyzed. Completion of this mentored project will allow me to gain in-depth expertise in areas such as novel delivery mechanisms such as gene therapy, detailed analysis of apoptotic pathways focusing on endothelial and tumor cell responses to antiangiogenic agents. This unique combination will allow me to complete the first phase of my career development and progress on to independent research.