BC Cancer Agency, Vancouver, British Columbia, Canada V5Z 4E6.
Cancer J. 2013 Jan-Feb;19(1):79-89. doi: 10.1097/PPO.0b013e3182801cf7.
Important inroads have been made in the understanding and treatment of metastatic prostate cancer in recent years. However, the need for agents targeting novel pathways remains ever present. One such area with promise is through apoptosis or programmed cell death. Many perturbations within the apoptotic process have been associated with treatment resistance and progression in castration-resistant prostate cancer; thus, therapeutic potential exists with agents that can restore an effective apoptotic response to cellular stressors. This article focuses on agents in clinical development targeting apoptosis through the intrinsic and extrinsic pathways. We review the current status of agents that intervene at the Bcl2 checkpoints, humanized antibodies to death receptors, agents that target the inhibitors of apoptosis proteins, mimetics of small mitochondria-derived activator of caspases, and antisense therapies targeting cytoprotective chaperones. Although single-agent activity has been demonstrated with some of these agents, the clinical development path forward will see them coupled with standard hormonal therapy and chemotherapy. OGX-011 (custirsen), which inhibits expression of the cytoprotective chaperone protein clusterin, is the most mature of these agents and is being tested in combination with chemotherapy in phase III clinical trials for castration-resistant prostate cancer, and results are eagerly awaited.
近年来，在转移性前列腺癌的理解和治疗方面取得了重要进展。然而，仍然需要针对新途径的药物。其中一个有前途的领域是通过细胞凋亡或程序性细胞死亡。细胞凋亡过程中的许多干扰与去势抵抗性前列腺癌的治疗耐药性和进展有关；因此，具有恢复细胞应激有效凋亡反应的药物具有治疗潜力。本文重点介绍了通过内在和外在途径靶向细胞凋亡的临床开发中的药物。我们回顾了干预 Bcl2 检查点的药物、针对死亡受体的人源化抗体、针对凋亡抑制蛋白的药物、模仿小线粒体衍生的半胱天冬酶激活物的模拟物以及针对细胞保护伴侣的反义治疗的现状。尽管这些药物中的一些已经显示出单药活性，但未来的临床开发方向将是将它们与标准激素治疗和化疗相结合。抑制细胞保护伴侣蛋白簇蛋白表达的 OGX-011（custirsen）是这些药物中最成熟的一种，正在进行与化疗联合治疗去势抵抗性前列腺癌的 III 期临床试验，结果备受期待。
