Effects of silencing RNAs for gastrin and CCK on human pancreatic cancer

胰腺癌是美国癌症相关死亡的第四大原因， 年生存率低于1%，仍是所有恶性肿瘤中最低的。预后的原因 ：或胰腺癌的低风险与无法在早期诊断这种恶性肿瘤有关， 因为它对标准化疗有抵抗力。我们的研究小组一直在研究 研究胰腺癌的生长调节，长期目标是设计早期治疗策略， 诊断和治疗。我们已经发现胰腺癌的生长在一定程度上是由 胃肠道肽胃泌素和胆囊收缩素（CCK）的自分泌产生，通过一种独特的 CCK受体。通过反义技术显著降低胃泌素的表达和产生 在培养物和动物模型中抑制胰腺癌生长， n肿瘤转移。最近一种使用短发夹RNA沉默RNA的方法已经显示出更好的效果。 比反义技术更有效，并具有治疗干预的潜力。我们的团队设计了， 开发并优化了聚乙二醇化阳离子脂质体递送系统， siRNA在肿瘤靶向模式。这项资助假设人类胰腺癌的生长可以 通过降低肽胃泌素和/或CCK的表达来抑制。为了验证这一假设， 提出了以下具体目标：1）消除胃泌素或CCK的产生，并对其起作用。 通过小发夹RNA沉默胰腺癌细胞CCK和胃泌素的表达 2）在原位杂交中体内分析表达胃泌素/CCK shRNA的胰腺癌细胞; 用于原发性肿瘤生长和转移的小鼠模型，和3）测试掺入神经酰胺的 脂质体，其被设计为在体外和体内将siRNA递送至胰腺癌细胞。这些研究是 申请人的长期目标是应用关于胰腺癌生长调节的知识 在细胞水平上应用到病人护理上。这些研究是将基础科学的结果连接起来的第一步 进入临床研究领域。如果在动物模型中证明有效，我们计划继续治疗 胰腺癌患者。

Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States and with the five- year survival rate of less than 1%, it remains the lowest of all malignancies. The reasons why the prognosis :or pancreatic cancer is poor are related to the inability to diagnose this malignancy in early stages and because of its resistance to standard chemotherapy. Our research group has been studying the mechanisms nvolving growth regulation of pancreatic cancer with the long-range goals of designing strategies for early diagnosis and treatment. We have found that growth of pancreatic cancer is in part regulated by the autocrine production of the gastrointestinal peptides gastrin and cholecystokinin (CCK) through a unique CCK receptor. Decreased expression and production of gastrin through antisense techniques significantly mpairs pancreatic cancer growth in culture and in animal models and is associated with a marked reduction n tumor metastases. Recently a method to silence RNA using short hairpin RNAs has been shown to more effective than antisense techniques and has potential for therapeutic intenvention. Our team has designed, developed and optimized a pegylated cationic liposome delivery system that has the capability of delivering siRNA in a tumor-targeted modality. This grant hypothesizes that growth of human pancreatic cancer can be inhibited by decreasing the expression of the peptides gastrin and / or CCK. In order to test this hypothesis, the following specific aims are proposed: 1) Abolition of gastrin or CCK production by, and action on,. pancreatic cancer cells through silencing of CCK and gastrin expression by shRNA (small hairpin RNA) technology; 2) Analyze the gastrin/CCK shRNA expressing pancreatic cancer cells in vivo in an orthotopic mouse model for primary tumor growth and metastasis, and 3) test the effect of ceramide-incorporated liposomes designed to deliver siRNA in vitro and in vivo to pancreatic cancer cells. These studies are part of the applicant's long-term goals to apply what has been learned about growth regulation of pancreatic cancer at the cellular level to patient care. These studies are the first step in bridging the results from basic science studies into the clinical realm. If shown to be effective in the animal model, we plan to proceed to treating subjects with pancreatic cancer.