Novel Theranostics for Pancreatic Cancer

胰腺癌的新型治疗学

基本信息

批准号：
8627945
负责人：
Julia Davydova
金额：
$ 33.2万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627945
关键词：
Adenoviruses Biodistribution Bystander Effect Cancer Detection Cancer Etiology Cancer Immunology Science Cancer Model Cancer Patient Capsid Proteins Carcinomatosis Cessation of life Clinical Clinical Trials Combined Modality Therapy Complication Detection Development Diagnosis Diagnostic Diagnostic Neoplasm Staging Disease Disease Management Distant Metastasis Dose Employment Excision Generations Genetic Genetic Engineering Goals Hamsters Human Human Adenoviruses Image Imagery Imaging Techniques Immunity Immunocompetent In Vitro Incidence Lesion Liver Malignant neoplasm of pancreas Malignant neoplasm of prostate Malignant neoplasm of thyroid Mediating Modality Modeling Modification Nature Neoplasm Metastasis Nude Mice Oncolytic Oncolytic viruses Operative Surgical Procedures Pathology Patients Peritoneal Phase I Clinical Trials Primary Neoplasm Production Radiation therapy Radioactive Iodine Radioisotopes Recurrence Research Route SLC5A5 gene Safety Sensitivity and Specificity Site Specificity Staging Structure Survival Rate Systemic disease Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Tissues Transgenes Translating Translational Research United States Unnecessary Surgery Unresectable Viral Viral Genes Work X-Ray Computed Tomography Xenograft procedure anticancer research base bioimaging bioluminescence imaging cancer cell cancer therapy clinical application conditionally replicative adenovirus design effective therapy imaging modality improved intraperitoneal men mouse model multi-component intervention neoplastic cell novel novel strategies novel therapeutics oncolysis overexpression pancreatic cancer cells pancreatic neoplasm promoter protein expression public health relevance single photon emission computed tomography sodium-iodide symporter success theranostics tool treatment strategy tumor uptake vector

项目摘要

Project Summary/Abstract 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 that practiced clinically with high efficacy for metastatic thyroid cancer. The structure of our CRAd is 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 will 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.

项目概要/摘要近年来，胰腺癌的发病率以惊人的速度增加。由于阴险且该疾病具有侵袭性，在就诊时 90% 以上的患者有局部或转移扩散妨碍根治性切除。因此，取得进展的一个关键要求是开发新的有效的胰腺癌治疗方法。诊断方面的改进促进癌症分期的工具有望推动治疗进展并优化疾病的管理。条件复制腺病毒（CRAds）的使用构成了一种有前途的替代方案癌症治疗。在这个提案中，我们结合了感染性抗肿瘤作用的优点增强的 CRAds、放射性碘治疗和基于无创放射性核素的成像来开发一种新的胰腺癌治疗和腹膜转移检测的方法。拟议的研究涉及生产表达治疗和成像的全新一代 CRAd 构建体转基因，人类碘化钠同向转运体（NIS），将诱导肿瘤吸收放射性碘细胞。 NIS 表达将允许通过腺病毒复制的可视化对疾病进行无创分期，但更重要的是，将允许使用与临床实践类似的放射性碘 131I 进行高效治疗用于转移性甲状腺癌。我们的 CRAd 的结构旨在克服当前载体的低效率并使它们对于全身给药来说是实用的。腺病毒复制仅在肿瘤中发生包含肿瘤特异性启动子，允许关键病毒基因的特异性递送。腺病毒六邻体改造将进一步减少肝隔离。与放射治疗相结合将协同增强病毒溶瘤作用。病毒复制的无创成像将提供转移检测和 CRAd 生物分布信息。为了模拟人类转移性疾病，通过原位或原位诱导的胰腺癌模型腹膜内肿瘤接种将与通过全身和腹膜内途径递送的载体一起使用。在除了裸鼠模型外，还有免疫活性的同基因仓鼠模型，它允许人类将测试腺病毒复制，以分析基于 CRAd 的放射性碘治疗的有效性和安全性成像。一种具有高度临床潜力的多模式疗法，结合了溶瘤病毒疗法、放射性碘疗法、基于这种新方法，可以为胰腺癌患者开发成像技术。该提案的成功产品可以迅速转化为临床领域，带来新颖和对胰腺癌患者（包括那些无法切除肿瘤的患者）进行有效的治疗。