Studies of Attenuated Salmonella with IL-2 against pancreatic cancer

描述(申请人提供)：胰腺癌是一种极具破坏性的疾病，预后极差，是美国癌症相关死亡的第四大原因。我们的实验室已经证明，在已建立的神经母细胞瘤、转移性骨肉瘤和腺癌转移的小鼠模型中，口服一次剂量的携带人类白细胞介素2(IL-2)基因工程的减毒鼠伤寒沙门氏菌能有效地显著减少局部晚期肿瘤的大小、重量和体积以及转移沉积的数量。沙门氏菌倾向于在肿瘤组织中积聚，但沙门氏菌发挥抗肿瘤作用的确切机制尚不清楚。我们假设，口服含有人IL-2基因的沙门氏菌(沙门氏菌-IL2)将在已建立的小鼠模型中显著减少原发胰腺癌的大小、重量和体积。此外，这种肿瘤破坏的机制是多模式的，可能包括(1)细胞免疫反应的局部增强，(2)肿瘤细胞中的凋亡途径的激活，(3)细胞营养物质的缺乏，以及(4)肿瘤血管供应的损害。我们与3位胰腺癌领域的专家(Selwyn M.Vickers博士、Ashok K.Saluja博士和Christopher A.Klug博士)建立了研究合作关系，他们都精通各种胰腺癌细胞模型。因此，本研究的总体目标是(1)研究沙门氏菌-IL2在建立的小鼠胰腺癌体内模型中的潜在抗肿瘤作用；(2)通过沙门氏菌-IL2的抗肿瘤作用来阐明其作用机制。公共卫生相关性：该研究项目的目标是开发和研究一种治疗胰腺癌的新形式的口服生物疗法。我们将把携带人类白细胞介素2基因的减毒鼠伤寒沙门氏菌注射给胰腺癌原发癌和转移癌模型的小鼠。我们将研究这种新型治疗剂的抗肿瘤潜力和机制。

DESCRIPTION (provided by applicant): Pancreatic cancer is a devastating disease with an extremely poor prognosis and is the fourth leading cause of cancer-related deaths in the United States. Our laboratory has shown that one oral dose of an attenuated strain of Salmonella typhimurium genetically engineered to carry the human gene for interleukin-2 (IL-2) (Salmonella-IL2) in established murine models of neuroblastoma, metastatic osteogenic sarcoma, and adenocarcinomatous metastases of the liver is effective in significantly reducing the size, weight, and volume in locally advanced tumors and the numbers of metastatic deposits. Salmonella tends to accumulate in tumor tissue, yet the exact mechanisms by which Salmonella imparts its antitumor effects are unknown. We hypothesize that orally administered Salmonella containing the human IL-2 gene (Salmonella-IL2) will significantly decrease the size, weight, and volume of primary pancreatic adenocarcinoma in an established murine model. Furthermore, the mechanisms behind this tumor destruction are multimodal and may include (1) local augmentation of the cellular immune response, (2) activation of an apoptotic pathway in tumor cells, (3) deprivation of cellular nutrients, and (4) impairment of the vascular supply to the tumor. We have an established research collaboration with 3 experts in the field of pancreatic carcinoma (Dr. Selwyn M. Vickers, Dr. Ashok K. Saluja, and Dr. Christopher A. Klug), all proficient in various pancreatic cancer cell models. Thus, the overall goals of this research program are (1) to investigate the potential antitumor role of Salmonella-IL2 in established in vivo murine models of pancreatic cancer and (2) to elucidate the mechanisms by with Salmonella-IL2 imparts its antitumor effect. PUBLIC HEALTH RELEVANCE: The objective of this research program is to develop and study a novel form of oral biotherapy for the treatment of pancreatic cancer. We will give attenuated Salmonella typhimurium which carries the human gene for interleukin-2 to mice in models of both primary and metastatic pancreatic cancer. We will study the antitumor potential and mechanisms of this novel therapeutic agent.