Novel Theranostics for Pancreatic Cancer

描述（由申请人提供）：近年来胰腺癌的发病率以惊人的速度增加。由于疾病的隐匿性和侵袭性，在呈现时，超过90%的患者具有局部或转移性扩散，排除了根治性切除。因此，进展的关键要求将是开发新的有效的胰腺癌治疗方式。改进诊断工具以促进癌症分期有望推进治疗进展并优化疾病管理。 条件复制型腺病毒（CRAds）的就业构成了一个有前途的替代癌症治疗。在这个提议中，我们联合收割机结合了感染性增强CRAds的抗肿瘤作用、放射性碘治疗和基于放射性核素的无创成像的优点，开发了一种用于胰腺癌治疗和腹膜转移检测的新方法。拟议的研究涉及生产一种全新的CRAd构建体，表达一种治疗和成像转基因，即人钠碘同向转运体（NIS），它将诱导肿瘤细胞摄取放射性碘。NIS表达将允许通过腺病毒复制的可视化对疾病进行非侵入性分期，但更重要的是，将允许用放射性碘131 I治疗，其类似于临床上实践的对转移性甲状腺癌具有高疗效的达特。 我们的CRAd的结构被设计为克服当前载体的低功效，并使它们对于系统性施用是实用的。腺病毒复制将通过包含允许特异性递送关键病毒基因的肿瘤特异性启动子而仅在肿瘤中发生。腺病毒六邻体修饰将进一步减少肝脏隔离。与放射治疗的联合将协同增强病毒溶瘤的效果。病毒复制的非侵入性成像将提供转移检测和CRAd生物分布信息。 为了模拟人转移性疾病，将使用通过原位或腹膜内肿瘤接种诱导的胰腺癌模型，其中载体通过全身和腹膜内途径递送。除裸鼠模型外，还将对允许人腺病毒复制的免疫活性同基因仓鼠模型进行检测，以分析基于CRAD的放射性碘治疗和成像的疗效和安全性。 基于这种新方法，可以为胰腺癌患者开发具有高临床潜力的多模式治疗，其结合了溶瘤病毒治疗，放射性碘治疗和成像技术。该提案的成功产品可以迅速转化为临床竞技场，为胰腺癌患者（包括不可切除的肿瘤患者）带来新颖有效的治疗方法。

DESCRIPTION (provided by applicant): The incidence of pancreatic cancer has increased at an alarming rate in recent years. Due to the insidious and aggressive nature of the disease, at the time of presentation more than 90% of patients have local or metastatic spread precluding curative resection. Thus, a critical requirement for progress will be the development of new and effective therapeutic modalities for pancreatic cancer. Improvements in diagnostic tools to facilitate the staging of cancer will be expected to advance the progress of treatment and optimize management of the disease. The employment of conditionally replicative adenoviruses (CRAds) constitutes a promising alternative for cancer treatment. In this proposal, we combine the advantages of the antitumor effect of infectivity enhanced CRAds, radioiodine therapy, and noninvasive radionuclide-based imaging to develop a novel approach for pancreatic cancer treatment and detection of peritoneal metastases. The proposed research involves production of an entirely new generation of CRAd constructs expressing a therapeutic and imaging transgene, the human sodium-iodide symporter (NIS), which will induce uptake of radioactive iodine by tumor cells. NIS expression will allow noninvasive staging of the disease through visualization of adenoviral replication, but more importantly, will allow therapy with radioiodine 131I similar to tat practiced clinically with high efficacy for metastatic thyroid cancer. The structure of our CRAd i designed to overcome low efficacy of current vectors and make them practical for systemic administration. Adenovirus replication will occur exclusively in tumors through the inclusion of a tumor specific promoter allowing specific delivery of critical viral genes. Adenovirus hexon modification will further reduce liver sequestration. Combination with radiotherapy will synergistically enhance the effect of viral oncolysis. Noninvasive imaging of viral replication wil provide both detection of metastases and CRAd biodistribution information. To mimic human metastatic disease, a pancreatic cancer model induced by either orthotopic or intraperitoneal tumor inoculation will be used with vectors delivered via systemic and intraperitoneal routes. In addition to a nude mouse model, an immunocompetent syngeneic hamster model, which permits human adenovirus replication, will be tested to analyze the efficacy and safety of CRAd-based radioiodine therapy and imaging. A multimodal therapy with high clinical potential that combines oncolytic viral therapy, radioiodine therapy, and imaging techniques can be developed for pancreatic cancer patients based on this novel approach. Successful products from this proposal can be promptly translated to the clinical arena bringing novel and effective therapies to the patients with pancreatic cancer including those with unresectable tumors.