Small molecular inhibitors of p-STAT3: novel agents for treatment of primary and metastatic CNS cancers.
Small molecular inhibitors of p-STAT3: novel agents for treatment of primary and metastatic CNS cancers.
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DOI：
10.2174/157488908786242489
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Priebe, Waldemar
中科院分区：
文献类型：
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作者：
Heimberger, Amy B;Priebe, Waldemar
高级别原发性和转移性中枢神经系统 (CNS) 肿瘤常见、致命且常规治疗难治，中位生存期不到一年。信号转导子和转录激活子 (STAT) 3 是一种关键的转录因子，是中枢神经系统肿瘤恶性肿瘤和转移的基本组成部分。 STAT3 通过增强增殖、血管生成、侵袭、转移和免疫抑制来促进肿瘤发生。专门针对中枢神经系统内恶性肿瘤的药物的临床实施显然是一个未满足的主要需求。一组有效的 STAT3 小分子抑制剂在小鼠模型（包括已形成的脑内肿瘤）中对恶性肿瘤显示出显着的疗效和最小的毒性。 STAT3 阻断剂的这种体内功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。鉴于它们能够实现良好的中枢神经系统渗透，这些药物将进入中枢神经系统恶性肿瘤患者的临床试验并作为免疫治疗增强剂。
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.