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: 8990457
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990457
• 关键词: Adenoviruses; Advanced Malignant Neoplasm; Affinity; Antineoplastic Agents; Binding Proteins; 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; Neoplasm Transplantation; Neoplasms; Oncogenes; Oncolytic; Oncolytic viruses; Operative Surgical Procedures; Organ; Outcome; Patients; Peptide Library; Production; 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 biomarkers; cancer cell; cancer therapy; 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; 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）：许多癌症患者在最初诊断时仍被发现患有晚期/扩散疾病。特别是胰腺癌是癌症相关死亡的第四大原因，只有不到10%的患者接受了手术切除。传播性疾病的治疗不能仅仅通过局部治疗来解决，这仍然是一个巨大的挑战。因此，对晚期癌症的新型全身治疗有很高的需求。与局部区域治疗相比，肿瘤基因治疗的全身应用需要更高效和选择性的基因传递，即使初始转导较低，也需要体现足够的抗肿瘤效果。溶瘤病毒已被用于治疗全身性疾病。腺病毒（Ad）表现出通过特异性蛋白与蛋白结合介导的高效体内转导，其指数复制导致肿瘤溶解。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，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，将功能配体并入病毒粒子是非常困难的。克服这一障碍的一种有希望的方法是从一开始就高通量筛选Ad衣壳形式的高多样性配体-肽库。最近，通过采用我们新颖的广告制作系统，我们已经实现了广告库多样性的急剧增加（5 x 109）。用表达胰腺癌标志物间皮素（msln）的细胞系对该文库进行高通量筛选，发现了一个靶向基序，对表达msln的细胞具有强效和选择性感染性。因此，高通量筛选高多样性Ad库是开发针对各种癌症的转导靶向载体的有力而实用的方法。与现有的溶瘤性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癌细胞的隔离，提供系统水平的肿瘤靶向以及肿瘤中的原位癌细胞靶向；2)高多样性的Ad库在复制能力平台上允许高通量的体外和体内直接筛选。在这个项目中，我们将开发能够全身治疗胰腺癌的溶瘤性广告。具有载体骨架的Ad纤维文库显示肝脏隔离减少，将在体外和体内进行高通量筛选。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。所得到的溶瘤病毒将首先在体外进行评估，然后在体内皮下肿瘤模型中进行评估。接下来，先导载体将在原位胰腺癌模型和患者肿瘤移植中进行评估。强效的全身注射溶瘤药Ad的开发将能够改善癌症患者的临床预后，包括那些不受重视的胰腺癌和其他肿瘤患者。