Next Generation Oncolytic Adenovirus for Advanced Pancreatic Cancer Treatment

用于晚期胰腺癌治疗的下一代溶瘤腺病毒

基本信息

批准号：
9188532
负责人：
MASATO YAMAMOTO
金额：
$ 31.54万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188532
关键词：
Adenoviruses Advanced Malignant Neoplasm Affinity Alpha Cell Antineoplastic Agents Binding Proteins Cancer Diagnostics Cancer Etiology Cancer Model Cancer Patient Capsid Carcinoma in Situ Cell Line Cells Cessation of life Clinical Code Daughter Development Diagnosis Disease Diversity Library Evaluation Excision Fiber Future Gene Delivery Generations Genetic Transcription Human In Situ In Vitro Injectable Lead Libraries Ligands Liver Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modification Neoplasm Transplantation Neoplasms Oncogenes Oncolytic Oncolytic viruses Operative Surgical Procedures Organ Outcome Patients Peptide Library Pharmacotherapy Production Proteins Reporting Research Personnel Structure System Systemic Therapy Systemic disease Transplant Recipients Unresectable Vertebral column Viral Genome Virion Virus Virus Assembly antitumor effect base cancer biomarkers cancer cell cancer therapy clinical development gene therapy high throughput screening improved in vivo in vivo Model mesothelin molecular drug target next generation novel novel therapeutics oncolysis pancreatic cancer cells promoter public health relevance screening subcutaneous success tumor vector

项目摘要

DESCRIPTION (provided by applicant): Many cancer patients are still found with advanced/spread diseases upon initial diagnosis. Particularly, pancreatic cancer is the 4th leading cause of cancer related death, and less than 10% of the patients are the subject of surgical resection. Treatment of spread disease, which cannot be handled solely by locoregional therapy, is still a big challenge. Thus, novel systemic treatment of advanced cancer is in high demand. Compared to loco-regional therapy, systemic application of cancer gene therapy mandates more efficient and selective gene delivery, and also needs to embody sufficient antitumor effect even with low initial transduction. Oncolytic viruses have been tried in systemic diseases. Adenovirus (Ad) shows efficient in vivo transduction mediated by specific protein-to-protein binding, and its exponential replication lead to oncolysis. If the vector distribution and transduction can be controlled, such a vector would overcome the obstacles for systemic delivery and enable the treatment of advanced cancer. However, incorporation of functional ligand into virus virion is extremely difficult due to interference of virus assembly or ligand affinity. One promising way to overcome this obstacle is high-throughput screening of the high-diversity ligand- peptide library in the format of Ad capsid from the beginning. Recently, we have achieved a drastic increase of Ad library diversity (5 x 109) by employing our novel Ad production system. High throughput screening of this library with a cell line expressing a pancreatic cancer marker, mesothelin (msln), identified a targeting motif showing potent and selective infectivity to msln expressing cells. Thus, high throughput screening of high diversity Ad library is a powerful and practical way to development transductionally targeted vectors for various cancers. Our system has two major benefits over existing oncolytic Ad systems: 1) transductional targeting and reduction of sequestration to non-cancer cells provides tumor targeting at systemic level as well as in situ cancer cell targeting in the tumor, and 2) a high diversity Ad-library in replication competent platform permits the high-throughput direct screening in vitro and in vivo. In this project, we will develop oncolytic Ads enabling systemic treatment of pancreatic cancer. The Ad fiber libraries with vector backbones showing reduced liver sequestration will undergo high throughput screening in vitro and in vivo. The identified capsid structures will be combined with promoter-based replication control for stringent cancer selectivity. The resultant oncolytic viruses will be assessed first in vitro and next in subcutaneous tumor model in vivo. Next, the lead vectors will be assessed in orthotopic pancreatic cancer models with cell lines and patient tumor transplants. The development of the potent and systemically-injectable oncolytic Ad will be able to improve the clinical outcome of the cancer patients, including those with unrespectable pancreatic cancer and other neoplasms.

描述（由申请人提供）：在初始诊断后仍发现许多癌症患者患有晚期/扩散疾病。特别是，胰腺癌是癌症相关死亡的第四个主要原因，不到10％的患者是手术切除的对象。无法完全通过局部疗法处理的传播疾病的治疗仍然是一个巨大的挑战。因此，晚期癌症的新型系统治疗需求很高。与Loco区域疗法相比，癌症基因治疗的全身应用要求更有效和选择性基因递送，并且即使初始转导较低，也需要体现足够的抗肿瘤效应。溶瘤病毒已在全身性疾病中尝试过。腺病毒（AD）显示出特定蛋白与蛋白质结合介导的有效的体内转导，其指数复制导致了脑分解。如果可以控制矢量分布和转导，那么这种矢量将克服全身传递的障碍，并能够治疗晚期癌症。但是，由于病毒组装或配体亲和力的干扰，将功能配体掺入病毒病毒中非常困难。克服这一障碍的一种有希望的方法是从一开始就以Ad Capsid的格式对高多样性配体肽库进行高通量筛选。最近，我们通过采用我们的新型广告生产系统实现了广告库多样性（5 x 109）的急剧增加。用表达胰腺癌标记物间皮素（MSLN）的细胞系对该文库进行高吞吐量筛选，鉴定出对MSLN表达细胞的有效感染性的靶向基序。因此，高多样性广告库的高吞吐量筛选是一种针对各种癌症开发针对靶向媒介的强大而实用的方法。我们的系统比现有的溶瘤AD系统具有两个主要好处：1）转导靶向和减少对非癌细胞的隔离靶向和减少肿瘤在全身性水平以及肿瘤中的原位癌细胞靶向靶向，以及2）复制的高度多样性广告能力在复制的平台中具有高度直接筛查的直接筛选。在这个项目中，我们将开发溶瘤广告，以实现胰腺癌的全身治疗。带有载体骨架的AD纤维库显示肝脏隔离减少，将在体外和体内进行高吞吐量筛查。确定的衣壳结构将与基于启动子的复制控制结合使用，以实现严格的癌症选择性。由此产生的溶瘤病毒将在体内首先在体外进行评估，其次是在体内皮下肿瘤模型中进行评估。接下来，将在具有细胞系和患者肿瘤移植的原位胰腺癌模型中评估铅载体。有效且可系统地注射的溶瘤广告的发展将能够改善癌症患者的临床结果，包括那些胰腺癌不可欣赏的患者和其他肿瘤。