Singh P, Uzgare A, Litvinov I, Denmeade S R, Isaacs J T
Chemical Therapeutics Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 1650 Orleans St. - CRB 162B, Baltimore, Maryland 21231, USA.
Endocr Relat Cancer. 2006 Sep;13(3):653-66. doi: 10.1677/erc.1.00797.
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.
前列腺癌的发生与雄激素受体（AR）轴的变化相关，这使其从对基质信号的旁分泌依赖性转变为前列腺癌细胞增殖和存活的自分泌起始信号。这种恶性转化是由于功能获得性改变，其中AR激活了正常前列腺上皮细胞中不存在的新的基因组（即转录）和非基因组信号通路。在进一步进展过程中，会发生额外的分子变化，使得即使在雄激素剥夺治疗后出现的低雄激素配体环境中，这些独特的依赖恶性肿瘤的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（如转录共激活因子）或非基因组（如类固醇受体共激活因子（Src）激酶）信号分子相互作用的结果。因此，需要一种抑制AR信号级联中多个点的联合雄激素受体靶向治疗（称为CART治疗），以防止每年约30000名美国男性在标准雄激素剥夺治疗失败后死亡。为了开发这种CART治疗，应将一系列针对AR级联中特定点的药物与标准雄激素剥夺治疗联合使用，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。作为开发这种CART治疗的初步方法，可以将多种新药与促黄体生成素释放激素类似物联合使用。这些药物包括：（1）5α-还原酶抑制剂，以抑制睾酮向更强效雄激素双氢睾酮的转化；（2）格尔德霉素类似物，以下调前列腺癌细胞中的AR蛋白；（3）“大分子”类固醇类似物，其可与AR结合并阻止其与其他共激活因子/信号分子相互作用；（4）小分子激酶抑制剂，以抑制作为恶性AR信号级联一部分而被激活的MEK。
