Gene Therapy for Prostate Cancer

前列腺癌的基因治疗

• 批准号: 6844300
• 负责人: Selvarangan Ponnazhagan
• 金额: $ 25.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-07 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844300
• 关键词: adeno associated virus group; angiogenesis inhibitors; angiostatins; athymic mouse; cell line; disease /disorder model; drug delivery systems; fibroblast growth factor; fibrosarcoma; gene expression; gene therapy; growth factor receptors; immunocytochemistry; immunologic assay /test; neoplastic process; nonhuman therapy evaluation; postmortem; prostate neoplasms; transfection /expression vector; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): The mortality associated with prostate cancer is primarily due to systemic dissemination of the disease to which conventional therapies such as surgery, androgen-depletion and chemotherapy fail to provide long-term cure. Thus, development of novel approaches is important for the treatment of both primary and metastatic prostate disease. Among the possible therapeutic targets, the tumor endothelium appears promising since endothelial cell growth during angiogenesis is crucial for tumor growth and metastasis. A majority of earlier studies using purified anti-angiogenic factors to modulate disease have been unsuccessful due to a requirement for constant administration, clinical side effects, and/or high cost. Thus, gene therapy approaches to achieve stable expression of anti-angiogenic factors in vivo have the potential to overcome many of these limitations. Recombinant adeno-associated virus (rAAV) vectors are a unique group of viruses that are less immunogenic than other viral vectors and arc integrating, hence, have greater advantage for long-term expression. We have recently shown that genetic transfer of an anti-angiogenic factor, sFlt-I abrogated the growth of human fibro sarcoma in nude mice. We also demonstrated with targeted-vectors, that high-efficiency, tumor cell-specific delivery is achievable. Further, by generating a genetically deficient transgenic adenocarcinoma mouse prostate cancer (TRAMP) model for the early growth response protein-I (Egr-l), we recently demonstrated a role for Egr-1 in delaying the progression of prostatic intra-epithelial neoplasia(PIN) to invasive carcinoma. Additional preliminary studies with rAAV encoding the anti-angiogenic factors human angiostatin, endostatin and sFlt-1 have shown protection against the growth of a human epithelial ovarian tumor cell line in athymic mice indicating the efficacy of AAV-mediated anti-angiogenic gene therapy. Based on these results, we hypothesize that gene therapy for prostate Cancer by AAV-mediated stable expression of anti-angiogenic factors will be efficacious both as a primary therapy, and as an adjuvant. Further, development of prostate cancer-specific rAAV containing anti-angiogenic genes would not only increase targeted-transduction but also minimize the vector dose and thus any associated toxicities. The present proposal will determine the efficacy of sustained anti-angiogenic gene therapy both as a primary therapy, and as an adjuvant therapy against recurrence in the TRAMP model. A successful outcome of these studies will form the basis for the development of Phase I clinical trials.

描述（由申请人提供）：与前列腺癌相关的死亡率主要是由于全身传播该疾病的疾病，例如手术，雄激素止动和化学疗法等常规疗法无法提供长期治愈。 因此，新方法的发展对于治疗原发性和转移性前列腺疾病至关重要。 在可能的治疗靶标中，由于血管生成过程中的内皮细胞生长对于肿瘤生长和转移至关重要，肿瘤内皮似乎很有希望。 大多数使用纯化的抗血管生成因子调节疾病的早期研究由于需要恒定给药，临床副作用和/或高成本而无法成功。 因此，在体内实现抗血管生成因子稳定表达的基因治疗方法具有克服许多局限性的潜力。重组腺相关病毒（RAAV）载体是一组独特的病毒，其免疫原性比其他病毒载体较小，因此，对于长期表达而言，具有更大的优势。 我们最近表明，抗血管生成因子的遗传转移，SFLT-I废除了裸鼠中人纤维肉瘤的生长。 我们还通过靶向向量证明，高效，肿瘤细胞特异性的递送是可以实现的。 此外，通过生成遗传缺陷的转基因腺癌​​小鼠前列腺癌（Tramp）模型，用于早期生长反应蛋白I（EGR-L），我们最近在延迟前列腺上皮内肿瘤的进展方面表现出了EGR-1的作用（引脚至浸润性癌。 RAAV编码抗血管生成因子的其他初步研究人血管生成因子，内胞霉素和SFLT-1已经显示了针对无胸腺小鼠中人类上皮卵巢肿瘤细胞系的生长的保护，这表明AAV介导的抗抗血管增生基因治疗的疗效。 基于这些结果，我们假设通过AAV介导的抗血管生成因子的稳定表达对前列腺癌的基因疗法将有效作为一种主要疗法，并且是辅助疗法。 此外，含有抗血管生成基因的前列腺癌特异性RAAV的发展不仅会增加靶向转移的剂量，而且还可以最大程度地减少载体剂量，从而最大程度地减少任何相关的毒性。 目前的建议将确定持续的抗血管生成基因疗法的疗效，既是一种主要的疗法，又是一种在流浪汉模型中反对复发的辅助治疗。 这些研究的成功结果将构成I期临床试验发展的基础。