Novel Theranostics for Pancreatic Cancer

胰腺癌的新型治疗学

基本信息

批准号：
8787718
负责人：
Julia Davydova
金额：
$ 31.9万
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/8787718
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 Health 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 accurate diagnosis anticancer research antitumor effect 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 non-invasive imaging novel novel strategies novel therapeutics oncolysis overexpression pancreatic cancer cells pancreatic neoplasm promoter protein expression radioiodine imaging radioiodine therapy single photon emission computed tomography sodium-iodide symporter success theranostics tool treatment strategy tumor uptake vector

项目摘要

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.

描述（申请人提供）：近年来，胰腺癌的发病率以惊人的速度增加。由于该疾病的隐匿性和侵袭性，在就诊时超过 90% 的患者已出现局部或转移性扩散，无法进行根治性切除。因此，进展的关键要求是开发新的有效的胰腺癌治疗方式。诊断工具的改进以促进癌症分期预计将推动治疗的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癌症治疗替代方案。在该提案中，我们结合了感染性增强的 CRAds 的抗肿瘤作用、放射性碘治疗和无创放射性核素成像的优点，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表达治疗和成像转基因的全新一代 CRAd 构建体，即人类碘化钠同向转运蛋白（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，类似于临床实践中对转移性甲状腺癌的高效治疗。我们的 CRAd i 的结构旨在克服当前载体的低功效，并使它们可用于全身给药。通过包含肿瘤特异性启动子，腺病毒复制将仅在肿瘤中发生，从而允许特定递送关键病毒基因。腺病毒六邻体修饰将进一步减少肝隔离。与放疗联合将协同增强病毒溶瘤效果。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，通过原位或腹膜内肿瘤接种诱导的胰腺癌模型将与通过全身和腹膜内途径递送的载体一起使用。除了裸鼠模型外，还将测试允许人类腺病毒复制的免疫活性同基因仓鼠模型，以分析基于 CRAd 的放射性碘治疗和成像的有效性和安全性。基于这种新方法，可以为胰腺癌患者开发一种具有高度临床潜力的多模式疗法，结合溶瘤病毒疗法、放射性碘疗法和成像技术。该提案的成功产品可以迅速转化为临床领域，为胰腺癌患者（包括那些患有不可切除肿瘤的患者）带来新颖有效的治疗方法。