Scher Howard I, Sawyers Charles L
Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
J Clin Oncol. 2005 Nov 10;23(32):8253-61. doi: 10.1200/JCO.2005.03.4777.
Prostate cancers that are progressing on medical and surgical therapies designed to ablate the action of androgens continue to express androgen receptor (AR) and to depend on signaling through the receptor for growth. A more clinically relevant classification of castration-resistant disease focuses on the mechanisms of receptor activation, which include (1) changes in the level of ligand(s) in tumor tissue; (2) increased levels of the protein due to gene amplification or altered mRNA expression; (3) activating mutations in the receptor that affect structure and function; (4) changes in coregulatory molecules including coactivators and corepressors; and (5) factors that lead to activation of the receptor independent of the level of ligand or receptor allowing kinase cross talk. From an AR perspective, the term "hormone refractory" is inappropriate. On the basis of this schema, we discuss strategies that are focused on the AR either directly or indirectly, as single agents or in combination, that are in clinical development.
旨在消除雄激素作用的药物和手术治疗下仍在进展的前列腺癌，继续表达雄激素受体（AR），并依赖通过该受体的信号传导来维持生长。去势抵抗性疾病更具临床相关性的分类侧重于受体激活机制，其中包括：（1）肿瘤组织中配体水平的变化；（2）由于基因扩增或mRNA表达改变导致蛋白质水平升高；（3）受体中影响结构和功能的激活突变；（4）包括共激活因子和共抑制因子在内的共调节分子的变化；以及（5）导致受体激活而与配体或受体水平无关从而允许激酶相互作用的因素。从AR的角度来看，“激素难治性”这一术语并不恰当。基于这一模式，我们讨论了在临床开发中直接或间接针对AR的策略，这些策略既可以作为单一药物，也可以联合使用。
