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

• 批准号: 8786530
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786530
• 关键词: Adenoviruses; Advanced Malignant Neoplasm; Affinity; Antineoplastic Agents; Cancer Diagnostics; Cancer Etiology; Cancer Model; Cancer Patient; Cancer cell line; 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; Health; Human; In Situ; In Vitro; Injectable; Lead; Libraries; Ligands; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modification; Molecular Target; Neoplasm Transplantation; Neoplasms; Oncogenes; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Organ; Outcome; Patients; Peptide Library; Pharmaceutical Preparations; Production; Protein Binding; Proteins; Reporting; Research Personnel; Staging; Structure; System; Systemic Therapy; Systemic disease; Transplant Recipients; Unresectable; Vertebral column; Viral Genome; Virion; Virus; Virus Assembly; antitumor effect; base; cancer cell; cancer therapy; gene therapy; high throughput screening; improved; in vivo; in vivo Model; mesothelin; next generation; novel; novel therapeutics; oncolysis; pancreatic cancer cells; promoter; screening; subcutaneous; success; tumor; vector

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）：许多癌症患者在初次诊断时仍然发现晚期/扩散性疾病。特别地，胰腺癌是癌症相关死亡的第四大原因，并且少于10%的患者是手术切除的对象。传播性疾病的治疗，不能仅仅通过局部治疗来处理，仍然是一个很大的挑战。因此，对晚期癌症的新型全身治疗的需求很高。 与局部区域治疗相比，癌症基因治疗的系统应用要求更有效和选择性的基因递送，并且还需要即使在低初始转导下也体现足够的抗肿瘤效果。溶瘤病毒已在系统性疾病中进行了尝试。腺病毒（Ad）通过特异性蛋白质间结合介导的体内转导，其指数复制导致溶瘤。如果能够控制载体的分布和转导，这种载体将克服全身递送的障碍，并能够治疗晚期癌症。然而，由于病毒装配或配体亲和力的干扰，将功能性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-肽库。最近，我们已经实现了广告库的多样性（5 × 109）通过采用我们的新的广告生产系统急剧增加。用表达胰腺癌标志物间皮素（mesothelin，msln）的细胞系高通量筛选该文库，鉴定了对表达mesln的细胞显示有效和选择性感染性的靶向基序。因此，高通量筛选高多样性Ad文库是开发用于各种癌症的转导靶向载体的有力且实用的方法。我们的系统与现有的溶瘤Ad系统相比具有两个主要优点：1）转导靶向和减少对非癌细胞的隔离提供了全身水平的肿瘤靶向以及肿瘤中的原位癌细胞靶向，以及2）复制能力平台中的高多样性Ad文库允许体外和体内的高通量直接筛选。 在该项目中，我们将开发能够系统治疗胰腺癌的溶瘤广告。具有显示减少的肝隔离的载体骨架的Ad纤维文库将在体外和体内进行高通量筛选。所鉴定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。首先在体外评估所得溶瘤病毒，然后在体内皮下肿瘤模型中评估。接下来，将在具有细胞系和患者肿瘤移植物的原位胰腺癌模型中评估先导载体。开发有效的和可全身注射的溶瘤Ad将能够改善癌症患者的临床结果，包括那些患有不值得注意的胰腺癌和其他肿瘤的患者。