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.

项目摘要/摘要近年来，胰腺癌的发病率增加了。由于阴险疾病的侵略性，在介绍时，超过90％的患者有局部或转移扩散排除治疗切除术。因此，进步的关键要求将是开发胰腺癌的新有效治疗方式。诊断的改进预计将促进癌症分期的工具可以提高治疗的进度并优化疾病的管理。有条件复制性腺病毒（Crads）的使用构成了有希望的替代方案癌症治疗。在此提案中，我们结合了感染性抗肿瘤作用的优势增强的Crads，放射性碘疗法和非侵入性放射性核素成像以开发新型胰腺癌治疗和腹膜转移检测的方法。拟议的研究涉及产生全新的Crad构建体，表达治疗和成像转基因，人类碘 - 碘分类剂（NIS），它将通过肿瘤诱导放射性碘摄取细胞。 NIS表达将允许通过可视化腺病毒复制的疾病无创分期，但更重要的是，将允许使用放射性碘131i进行治疗，类似于临床实践的疗效用于转移性甲状腺癌。我们的Crad的结构旨在克服当前向量的低功效并使它们系统管理的实用性。腺病毒复制将仅在肿瘤中通过包括肿瘤特异性启动子，允许特定的关键病毒基因递送。腺病毒hexon 修饰将进一步减少肝脏隔离。与放射疗法的结合将协同增强病毒肿瘤的作用。病毒复制的非侵入性成像将既可以检测转移和CRAD生物分布信息。模仿人类转移性疾病，这是一种原位或原位诱导的胰腺癌模型腹膜内肿瘤接种将用于通过全身和腹膜途径传递的向量。在增加了裸鼠模型，即免疫能力的合成仓鼠模型，该模型允许人类腺病毒复制将进行测试，以分析基于Crad的放射性碘治疗的功效和安全性成像。具有高临床潜力的多模式疗法，结合了溶瘤病毒疗法，放射性碘治疗，可以根据这种新方法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，带来小说，对胰腺癌患者的有效疗法，包括患有无法切除的肿瘤的患者。