Combinatorial androgen receptor targeted therapy for prostate cancer.
Combinatorial androgen receptor targeted therapy for prostate cancer.
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DOI：
10.1677/erc.1.00797
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发表时间：
2006-09
影响因子：
3.9
通讯作者：
Pratap Singh;A. Uzgare;Ivan V. Litvinov;S. Denmeade;John T. Isaacs
中科院分区：
文献类型：
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作者：
Pratap Singh;A. Uzgare;Ivan V. Litvinov;S. Denmeade;John T. Isaacs
前列腺癌的发生与雄激素受体 (AR) 轴的变化有关，雄激素受体 (AR) 轴从依赖基质信号的旁分泌转变为自分泌启动的前列腺癌细胞增殖和存活的信号。这种恶性转化是由于功能变化的获得，其中 AR 激活了新的基因组（即转录）和非基因组信号通路，而这些信号通路在正常前列腺上皮细胞中不存在。在进一步进展过程中，会发生额外的分子变化，即使在雄激素消融治疗后存在的低雄激素配体环境中，这些独特的恶性肿瘤依赖性 AR 信号通路也能被激活。这些信号通路是 AR 与一系列其他基因组（例如转录共激活因子）或非基因组（例如类固醇受体共激活因子 (Src) 激酶）信号分子配合的结果。因此，需要一种抑制 AR 信号级联中多个点的组合雄激素受体靶向疗法（称为 CART 疗法），以防止每年约 30,000 名美国男性因标准雄激素消融疗法失败而死亡。为了开发这种 CART 疗法，一系列针对 AR 级联中特定点的药物应与标准雄激素消融疗法结合使用，以确定产生最大治疗性抗前列腺癌效果所需的最少药物数量。作为开发此类 CART 疗法的初步方法，多种新药可以与黄体生成素释放激素类似物结合使用。这些包括： (1) 5α-还原酶抑制剂，抑制睾酮转化为更有效的雄激素二氢睾酮； (2) 格尔德霉素类似物可下调前列腺癌细胞中的 AR 蛋白，(3) “大体积”类固醇类似物，可与 AR 结合并阻止其与其他共激活剂/信号分子合作，以及 (4) 小分子激酶抑制剂可抑制 MEK，MEK 作为恶性 AR 信号级联的一部分被激活。
Prostatic carcinogenesis is associated with changes in the androgen receptor (AR) axis converting it from a paracrine dependence upon stromal signaling to an autocrine-initiated signaling for proliferation and survival of prostatic cancer cells. This malignant conversion is due to gain of function changes in which the AR activates novel genomic (i.e. transcriptional) and non-genomic signaling pathways, which are not present in normal prostate epithelial cells. During further progression, additional molecular changes occur which allow these unique malignancy-dependent AR signaling pathways to be activated even in the low androgen ligand environment present following androgen ablation therapy. These signaling pathways are the result of partnering the AR with a series of other genomic (e.g. transcriptional co-activators) or non-genomic (e.g. steroid receptor co-activator (Src) kinase) signaling molecules. Thus, a combinatorial androgen receptor targeted therapy (termed CART therapy) inhibiting several points in the AR signaling cascade is needed to prevent the approximately 30,000 US males per year dying subsequent to failure of standard androgen ablation therapy. To develop such CART therapy, a series of agents targeted at specific points in the AR cascade should be used in combination with standard androgen ablative therapy to define the fewest number of agents needed to produce the maximal therapeutic anti-prostate cancer effect. As an initial approach for developing such CART therapy, a variety of new agents could be combined with luteinizing hormone-releasing hormone analogs. These include: (1) 5alpha-reductase inhibitors to inhibit the conversion of testosterone to the more potent androgen, dihydrotestosterone; (2) geldanamycin analogs to downregulate AR protein in prostate cancer cells, (3) 'bulky' steroid analogs, which can bind to AR and prevent its partnering with other co-activators/signaling molecules, and (4) small molecule kinase inhibitors to inhibit MEK, which is activated as part of the malignant AR signaling cascade.