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

胰腺癌是美国与癌症相关的死亡的第四大原因，而在美国， 年生存率不到1%，它仍然是所有恶性肿瘤中最低的。为什么预后不佳？ ：或胰腺癌很差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这种机制 探讨胰腺癌生长调控与早期治疗策略的远期目标 诊断和治疗。我们发现胰腺癌的生长在一定程度上受 胃肠道多肽胃泌素和胆囊收缩素(CCK)的自分泌通过独特的 CCK受体。反义技术显著降低胃泌素的表达和产量 在培养和动物模型中胰腺癌的生长，并与显著减少相关 肿瘤转移N例。最近，一种使用短发夹状RNA沉默RNA的方法被证明是更多的 比反义技术有效，并具有治疗意图的潜力。我们团队设计了， 聚乙二醇化阳离子脂质体给药系统的研制与优化 以肿瘤为靶向的siRNA。这项拨款假设人类胰腺癌的生长可以是 通过减少胃泌素和/或CCK多肽的表达来抑制。为了检验这一假设， 建议的具体目标如下：1)废除胃泌素或CCK的生产，并对其采取行动。 ShRNA沉默胰腺癌细胞CCK和胃泌素的表达 2)原位分析胰腺癌细胞体内表达胃泌素/CCK shRNA 建立小鼠原发肿瘤生长和转移模型；3)检测神经酰胺的作用 设计用来在体外和体内向胰腺癌细胞运送siRNA的脂质体。这些研究是 申请者的长期目标是应用已知的胰腺癌生长调控知识 在细胞水平上对病人的护理。这些研究是连接基础科学成果的第一步 对临床领域的研究。如果在动物模型中被证明是有效的，我们计划继续治疗 胰腺癌的受试者。

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.