Heimberger Amy B, Priebe Waldemar
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Recent Pat CNS Drug Discov. 2008 Nov;3(3):179-88. doi: 10.2174/157488908786242489.
High-grade primary and metastatic central nervous system (CNS) tumors are common, deadly, and refractory to conventional therapy and have a median survival duration of less than one year. A key transcriptional factor, signal transducer and activator of transcription (STAT) 3, drives the fundamental components of tumor malignancy and metastases in the CNS. STAT3 promotes this tumorigenesis by enhancing proliferation, angiogenesis, invasion, metastasis, and immunosuppression. The clinical implementation of drugs that specifically target malignancy within the CNS is clearly a major unmet need. A group of potent, small molecule inhibitors of STAT3 display marked efficacy with minimal toxicity against malignancy in murine models, including established intracerebral tumors. The mechanism of this in vivo efficacy of the STAT3 blockade agents is a combination of direct tumor cytotoxicity and immune cytotoxic clearance. Given their ability to achieve good CNS penetration, these drugs will be taken forward into clinical trials for patients with CNS malignancies and as immunotherapeutic enhancers.
高级别原发性和转移性中枢神经系统（CNS）肿瘤常见、致命且对传统治疗难治，中位生存期不到一年。关键转录因子信号转导与转录激活因子（STAT）3驱动CNS肿瘤恶性和转移的基本成分。STAT3通过增强增殖、血管生成、侵袭、转移和免疫抑制来促进这种肿瘤发生。专门针对CNS内恶性肿瘤的药物的临床应用显然是一个重大未满足需求。一组有效的STAT3小分子抑制剂在小鼠模型中对恶性肿瘤显示出显著疗效且毒性极小，包括已建立的脑内肿瘤。STAT3阻断剂这种体内疗效的机制是直接肿瘤细胞毒性和免疫细胞毒性清除的结合。鉴于它们具有良好的CNS穿透能力，这些药物将推进到针对CNS恶性肿瘤患者的临床试验中，并作为免疫治疗增强剂。
