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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(申请人提供)：许多癌症患者在初步诊断时仍发现有晚期/播散性疾病。特别是，胰腺癌是癌症相关死亡的第四大原因，只有不到10%的患者是手术切除的对象。传播疾病的治疗仍然是一个巨大的挑战，这不能仅仅通过局部治疗来解决。因此，对晚期癌症的新的系统治疗是非常需要的。与局部治疗相比，肿瘤基因治疗的全身性应用要求更高效、更有选择性的基因传递，而且即使在低初始转导的情况下也需要体现足够的抗肿瘤效果。溶瘤病毒已经在系统性疾病中进行了试验。腺病毒(Ad)通过特异的蛋白结合介导有效的体内转导，其指数性复制导致肿瘤溶解。如果能够控制载体的分布和转导，这样的载体将克服全身输送的障碍，并使晚期癌症的治疗成为可能。然而，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粒子是极其困难的。克服这一障碍的一个有希望的方法是从一开始就以Ad衣壳的形式高通量地筛选高多样性的配体-多肽文库。最近，我们通过使用我们的新型广告制作系统，实现了广告库多样性的急剧增加(5x109)。用表达胰腺癌标记物间皮蛋白(Msln)的细胞系对该文库进行高通量筛选，鉴定出一个靶向基序，该基序对表达msln的细胞具有有效和选择性的感染性。因此，高通量筛选高多样性的Ad文库是开发针对各种癌症的转导靶向载体的一种有效和实用的方法。与现有的溶瘤Ad系统相比，我们的系统有两个主要优点：1)转导靶向和减少对非肿瘤细胞的隔离提供了系统水平的肿瘤靶向和肿瘤内的原位肿瘤靶向；2)复制能力强的平台中的高度多样性的Ad文库允许高通量直接在体外和体内进行筛选。在这个项目中，我们将开发能够系统治疗胰腺癌的溶瘤ADS。载体骨架显示肝隔离减少的Ad纤维文库将在体外和体内进行高通量筛选。识别出的衣壳结构将与基于启动子的复制控制相结合，以实现严格的癌症选择性。产生的溶瘤病毒将首先在体外进行评估，然后在皮下肿瘤模型中进行体内评估。接下来，将在原位胰腺癌细胞系模型和患者肿瘤移植模型中对先导载体进行评估。有效的、可系统注射的溶瘤Ad的开发将能够改善癌症患者的临床结果，包括那些不受尊重的胰腺癌和其他肿瘤患者。