Targeted Polymer-Adenovirus Hybrids for Ablation of Bladder Cancer Disease

用于消融膀胱癌疾病的靶向聚合物腺病毒杂交体

基本信息

批准号：
7992229
负责人：
Kaushal Rege
金额：
$ 20.22万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-19 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992229
关键词：
Ablation Accounting Adenocarcinoma Adenovirus Vector Adenoviruses Animal Model Antibodies Apoptosis Binding Biodistribution Bladder Tissue Blood Platelets CAR receptor Cancer cell line Cell Death Cell Line Cessation of life Combined Modality Therapy Complex Development Disease Engineering Epidermal Growth Factor Receptor Erythrocytes Evaluation Eye Gene Delivery Generations Genes Heparin Hepatocyte Hepatotoxicity Hybrids Immunoconjugates In Vitro Induction of Apoptosis Injection of therapeutic agent Intravesical Instillation Invaded Lesion Libraries Liver Lung Lymphatic System Malignant - descriptor Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Methods Modeling Muscle Natural Immunity Neoplasm Metastasis Non-Malignant Oncogenes Outcome Patients Phenotype Polymers Proteins Radical Cystectomy Recurrence Research Residual state Serum Proteins Solutions Squamous cell carcinoma Superficial Lesion Surface System TNFSF10 gene Therapeutic Thermodynamics Tissues Toxic effect Transitional Cell Carcinoma Transurethral Resection Treatment Efficacy Tropism United States Urogenital Cancer Virus adenovirus receptor advanced disease antibody conjugate base bone cancer cell cytotoxicity effective therapy follow-up gene delivery system gene therapy high risk hybrid gene immunogenicity improved in vivo intravesical non-viral gene delivery novel novel strategies novel therapeutics public health relevance research study treatment strategy tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): The proposed research describes the development of adenovirus-based gene delivery vectors for the targeted ablation of advanced bladder cancer disease. Bladder cancer is the second most common cancer of the urogenital tract with over 68,000 new cases and 14,000 deaths in 2008. The majority of bladder cancers in the US are transitional cell carcinomas (TCC), although squamous cell carcinomas (SCC) and adenocarcinomas also occur. Superficial lesions are removed surgically by transurethral resection but since residual lesions have a high risk of recurrence (>80%) and progression (~50%), patients receive additional intravesical therapy. Long-term follow up shows that one-third of the patients who initially had superficial lesions die of bladder cancer. Radical cystectomy is the only therapeutic choice for recurrent superficial cancer or muscle invasive bladder cancer. Disease that has invaded beyond the muscle wall, spreads via the lymphatic system forming metastases in liver, lung or bone. Multimodal therapy of advanced tumors results in only 20-40% survival at 5 years. Thus, effective treatment strategies aimed at reducing the recurrence and progression of superficial bladder cancer, as well as improving therapeutic outcome in patients with advanced disease, are needed. Gene therapy using adenoviruses is a powerful approach for delivering exogenous genes that transcribe toxic proteins leading to the ablation of cancer cells. While this is an attractive approach, low expression of the Coxsackie-Adenovirus receptor (CAR) in advanced bladder cancer cells results in poor transduction of cancer cells but not normal hepatocytes, which results in liver toxicity of systemically delivered adenoviruses. In addition, immunogenicity of adenoviruses is a cause for concern. It is necessary to develop novel approaches for efficacious gene therapy of bladder cancer disease. We propose a hybrid system based on polymer-antibody immunoconjugates or PICs, and adenoviruses (Ad) for the targeted ablation of bladder cancer cells. Novel cationic polymers will be conjugated to anti-EGFR antibodies in order to target the Epidermal Growth Factor Receptor (EGFR), which is over-expressed on advanced bladder cancer cells. PICs will be complexed with Ad-GFP and Ad-TRAIL viruses and the in vitro transduction efficacy of the resulting PIC-adenovirus hybrids (PAHs) will be evaluated using bladder cancer cell lines. Cell lines that capture the advanced bladder cancer phenotype will be employed in the proposed studies. AdGFP-based PAHs will be used to determine infectivity (using GFP expression). AdTRAIL-based PAHs will be investigated for their apoptosis-inducing efficacy following the expression of TRAIL, which has been shown to demonstrate selectivity for inducing apoptosis in cancer cells. Three PICs selected from these in vitro experiments will be employed in an orthotopic animal model of bladder cancer to study the biodistribution and anti-tumor efficacy of the PAH. It is anticipated that the proposed strategy will result in the identification of novel therapeutics for the safe, effective, and targeted ablation of bladder cancer disease. PUBLIC HEALTH RELEVANCE: The overall aim of the proposed research is to develop highly effective adenovirus-based gene delivery methods for the ablation of advanced bladder cancer disease. Advanced bladder cancer disease accounts for over 68,000 new cases and 14,000 deaths every year in the United States. We hypothesize that polymer-immunoconjugates (PICs) can be employed in order to selectively target malignant bladder tissue and overcome the limitations associated with currently existing adenoviral cancer gene therapy systems.

描述（由申请人提供）：拟议的研究描述了基于腺病毒的基因传递载体的开发，用于靶向消融晚期膀胱癌疾病。膀胱癌是泌尿生殖道第二常见的癌症，2008 年有超过 68,000 例新发病例和 14,000 例死亡。美国的大多数膀胱癌是移行细胞癌 (TCC)，但也有鳞状细胞癌 (SCC) 和腺癌发生。通过经尿道切除术切除浅表病变，但由于残留病变具有很高的复发风险（>80%）和进展风险（~50%），因此患者需要接受额外的膀胱内治疗。长期随访显示，最初出现浅表病变的患者中有三分之一死于膀胱癌。根治性膀胱切除术是复发性浅表癌或肌层浸润性膀胱癌的唯一治疗选择。侵入肌肉壁以外的疾病通过淋巴系统扩散，在肝、肺或骨中形成转移。晚期肿瘤的多模式治疗导致 5 年生存率仅为 20-40%。因此，需要旨在减少浅表性膀胱癌的复发和进展以及改善晚期疾病患者的治疗结果的有效治疗策略。使用腺病毒的基因治疗是一种传递外源基因的有效方法，外源基因可转录有毒蛋白质，从而消除癌细胞。虽然这是一种有吸引力的方法，但晚期膀胱癌细胞中柯萨奇腺病毒受体（CAR）的低表达导致癌细胞的转导不良，但正常肝细胞则不然，从而导致全身递送的腺病毒产生肝毒性。此外，腺病毒的免疫原性也令人担忧。有必要开发膀胱癌疾病有效基因治疗的新方法。我们提出了一种基于聚合物抗体免疫偶联物或 PIC 和腺病毒 (Ad) 的混合系统，用于靶向消融膀胱癌细胞。新型阳离子聚合物将与抗 EGFR 抗体结合，以靶向在晚期膀胱癌细胞中过度表达的表皮生长因子受体 (EGFR)。 PIC 将与 Ad-GFP 和 Ad-TRAIL 病毒复合，并使用膀胱癌细胞系评估所得 PIC-腺病毒杂交体 (PAH) 的体外转导功效。捕获晚期膀胱癌表型的细胞系将用于拟议的研究。基于 AdGFP 的 PAH 将用于确定感染性（使用 GFP 表达）。在 TRAIL 表达后，将研究基于 AdTRAIL 的 PAH 的细胞凋亡诱导功效，TRAIL 已被证明具有诱导癌细胞凋亡的选择性。从这些体外实验中选择的三种 PIC 将用于膀胱癌原位动物模型，以研究 PAH 的生物分布和抗肿瘤功效。预计所提出的策略将导致确定安全、有效和靶向消融膀胱癌疾病的新疗法。公共健康相关性：拟议研究的总体目标是开发高效的基于腺病毒的基因传递方法，以消除晚期膀胱癌疾病。在美国，晚期膀胱癌每年导致超过 68,000 例新发病例和 14,000 例死亡。我们假设可以采用聚合物免疫缀合物（PIC）来选择性地靶向恶性膀胱组织并克服与当前现有的腺病毒癌症基因治疗系统相关的局限性。