Novel Theranostics for Pancreatic Cancer

胰腺癌的新型治疗学

• 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
• 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

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长。由于该疾病的隐匿性和侵袭性，在出现时超过90%的患者有局部或转移性扩散，无法进行根治性切除。因此，对进展的一个关键要求将是开发新的和有效的胰腺癌治疗方式。在诊断工具的改进，以促进癌症的分期将有望推进治疗的进展和优化管理的疾病。条件复制腺病毒（CRAds）是一种很有前途的癌症治疗方法。在本研究中，我们将感染性增强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势结合起来，开发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全新一代的CRAd构建物，表达一种治疗和成像转基因，即人碘化钠同调体（NIS），它将诱导肿瘤细胞摄取放射性碘。NIS的表达将允许通过腺病毒复制的可视化来进行疾病的无创分期，但更重要的是，将允许使用放射性碘131I治疗，类似于临床对转移性甲状腺癌的高效治疗。我们设计的CRAd结构旨在克服当前载体的低效率，使其适用于系统管理。腺病毒复制将只发生在肿瘤中，通过包含肿瘤特异性启动子，允许关键病毒基因的特异性传递。腺病毒六邻体修饰将进一步减少肝隔离。联合放疗可协同提高病毒溶瘤效果。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，将使用原位或腹腔肿瘤接种诱导的胰腺癌模型，并通过全身和腹腔途径传递载体。除了裸鼠模型外，还将测试一种允许人类腺病毒复制的具有免疫能力的同基因仓鼠模型，以分析基于cra的放射性碘治疗和成像的有效性和安全性。结合溶瘤病毒治疗、放射性碘治疗和影像学技术的多模式治疗可在此基础上为胰腺癌患者开发出具有较高临床潜力的治疗方法。该方案的成功产品可以迅速转化为临床领域，为包括不可切除肿瘤在内的胰腺癌患者带来新颖有效的治疗方法。