GENETIC RADIOIMMUNOTHERAPY OF PANCREATIC CANCER

描述(申请人摘要)：胰腺癌的死亡率为90% 由于疾病在当地/区域地点和 转移到远处的部位。申请人提议开发一种新的 结合基因治疗和放射性配基优点的治疗 技术目前人类放射免疫治疗的局限性反映了 肿瘤抗原低表达和抗体对肿瘤穿透的限制 分子。申请人建议开发基因治疗载体以诱导 肿瘤细胞高水平表达高亲和力的膜受体 用于可构建为携带放射性同位素的多肽配体。这些 配体是低分子的，可以增强肿瘤的穿透能力 利用将辐射辐射到几个肿瘤细胞直径的同位素 (距离)补偿不到普遍的肿瘤细胞转染率 费率。申请者将使用小鼠模型处理当地的肿瘤部位 使用肿瘤内和全身载体策略对人类胰腺癌进行治疗。 放射性标记多肽在转移部位的定位研究将 利用小鼠肝转移模型和全身给药 嗜性修饰腺病毒或受控制的腺病毒 肿瘤特异性启动子。适当的设计和测试 将同时开发放射性标记配体以优化剂量， 时间表、生物分布、治疗和毒性问题。这些研究将 开发这一独特的基因治疗/放射治疗范例，它将 为其他癌症的治疗提供有价值的信息。

DESCRIPTION (Applicant's Abstract): Pancreatic cancer has a 90% mortality rate due to progression of disease at both the local/regional site and metastases to distant sites. The applicant proposes to develop a new treatment which combines the benefits of gene therapy and radioligand technology. The current limitations of radioimmunotherapy in man reflect low tumor antigen expression and restricted tumor penetration of antibody molecules. The applicant proposes to develop gene therapy vectors to induce tumor cells to express high levels of membrane receptors with high affinity for peptide ligands which can be constructed to carry radioisotopes. These ligands are low molecular weight to enhance tumor penetration and will utilize isotopes which deliver radiation to several tumor cell diameters (distance) to compensate for less than universal tumor cell transfection rates. The applicant will address the local tumor site using murine models of human pancreatic cancer using intratumor and systemic vector strategies. Studies of localization of radiolabeled peptides in metastatic sites will utilize a murine hepatic metastases model and systemic administration of tropism-modified adenoviruses or adenoviruses under the control of tumor-specific promoters. The design and testing of appropriate radiolabeled ligands will be developed concurrently to optimize dose, schedule, biodistribution, therapy, and toxicity issues. These studies will develop this unique paradigm of gene therapy/radiation therapy which will provide information valuable to therapy of other cancers as well.