Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Curr Gene Ther. 2011 Jun;11(3):155-80. doi: 10.2174/156652311795684722.
The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of 15-18 months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.
成人中最常见的原发性脑肿瘤是胶质母细胞瘤。这些肿瘤具有高度侵袭性和侵略性，从诊断到死亡的平均存活时间为 15-18 个月。目前的治疗方法无法显著延长胶质母细胞瘤患者的生存时间。因此，神经胶质瘤是开发利用基因治疗的新型治疗方法的有吸引力的靶点。这篇综述将检查现有的神经胶质瘤临床前模型，包括异种移植物、同基因和遗传模型。目前正在临床前研究中探索几种有前途的治疗靶点。这些靶点将根据作用机制进行审查，即条件细胞毒性、靶向毒素、溶瘤病毒、肿瘤抑制基因/癌基因和免疫刺激方法。临床前基因治疗模式旨在确定哪些策略将提供快速的肿瘤消退和长期的复发保护。虽然正在进行广泛的潜在靶点的临床前研究，但只有最有效的靶点才会进一步转化为临床试验模式。总结了迄今为止报告的临床试验，包括条件细胞毒性、靶向毒素、溶瘤病毒和癌基因靶向方法的结果。临床试验结果并不像临床前模型预测的那样强劲；这可能是由于所采用的 GBM 模型的局限性所致。一旦解决了这个问题，并且我们在更好地模拟临床情况的模型中开发出有效的基因治疗方法，基因治疗将为治疗和管理脑肿瘤提供一种强大的方法。
