Novel Theranostics for Pancreatic Cancer

胰腺癌的新型治疗学

• 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
• 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

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，胰腺癌的发病率以惊人的速度增长。由于阴险的 和侵袭性的疾病，在出现时，90%以上的患者有局部或 转移的扩散排除了根治性切除。因此，取得进展的一个关键要求将是 胰腺癌新的有效治疗方法的发展。诊断方面的改进 促进癌症分期的工具有望推动治疗进展和优化 疾病的管理。 条件复制型腺病毒(CRAds)的应用构成了一种很有前途的替代方案 癌症治疗。在这项建议中，我们结合了抗肿瘤感染性作用的优势 增强型CRAds、放射性碘治疗和基于放射性核素的非侵入性成像开发一种新的 胰腺癌治疗和腹膜转移检测的方法。拟议的研究 涉及生产全新一代CRAd结构，表达治疗和成像 转基因，人钠碘转运体(NIS)，将诱导肿瘤摄取放射性碘 细胞。NIS的表达将通过对腺病毒复制的可视化来实现疾病的非侵入性分期， 但更重要的是，将允许使用放射性碘131I进行类似于临床实践的高效治疗。 治疗转移性甲状腺癌。 我们的CRAd的结构是为了克服电流载体的低效并使它们 适用于系统管理。腺病毒复制将仅发生在肿瘤中，通过 包括肿瘤特异性启动子，允许关键病毒基因的特定传递。腺病毒六邻体 修改后将进一步减少肝脏的隔离。与放射治疗相结合将协同增强 病毒溶瘤的效果。病毒复制的非侵入性成像将提供对转移的检测 和CRAd生物分布信息。 为了模拟人类转移性疾病，建立了一种原位或非原位诱导的胰腺癌模型 将使用通过全身和腹膜途径输送的载体进行腹膜内肿瘤接种。在……里面 除了裸鼠模型，免疫活性同基因仓鼠模型，它允许人类 腺病毒复制，将进行测试，以分析基于CRAd的放射性碘治疗的有效性和安全性 成像。 一种具有高临床潜力的多模式治疗，结合了溶瘤病毒治疗，放射性碘治疗， 基于这种新的方法，可以为胰腺癌患者开发成像技术。 这一建议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，包括不能切除的肿瘤患者的有效治疗。