Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on.
Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on.
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DOI：
10.3390/cancers13030509
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发表时间：
2021-01-29
期刊：
影响因子：
5.2
通讯作者：
McEwan IJ
中科院分区：
文献类型：
--
作者：
Estébanez-Perpiñá E;Bevan CL;McEwan IJ
前列腺癌是世界范围内男性中第二常见的癌症，每年有近130万新发病例，并且在未来二十年中，预计发病率和死亡率几乎翻一番。几十年来，这种致命的疾病已经或多或少成功地使用激素治疗，其最终目的是抑制雄激素信号传导。然而，前列腺肿瘤可以以许多不同的方式逃避这种激素治疗，并且治疗抗性疾病，所谓的去势抵抗性前列腺癌（CRPC）是主要的临床问题。有些违反直觉的是，雄激素受体仍然是CRPC的关键治疗靶点。在这里，我们解释了为什么会出现这种情况，并总结了新的激素治疗策略和最新进展的知识雄激素受体的结构和功能，支持他们。前列腺癌（PCa）是西方男性中除皮肤癌外最常见的癌症，占美国男性癌症诊断的四分之一以上。在1941年的一篇开创性论文中，Huggins和Hodges证明前列腺肿瘤和转移性疾病对雄激素的存在或缺乏敏感。因此，前列腺癌的第一种激素治疗是去势。在随后的八十年里，靶向雄激素信号传导轴，在可能的情况下使用药物而不是手术，已经成为治疗晚期和转移性疾病的支柱。雄激素信号通过雄激素受体，配体激活的转录因子，这是许多这类药物的直接目标。在这篇综述中，我们讨论了雄激素受体在前列腺癌中的作用，以及如何将结构信息和功能筛选相结合，继续用于发现新的药物来关闭受体或修改其在癌细胞中的功能。
Prostate cancer is the second most common cancer in men world-wide, with nearly 1.3 million new cases each year, and over the next twenty years the incidence and death rate are predicted to nearly double. For decades, this lethal disease has been more or less successfully treated using hormonal therapy, which has the ultimate aim of inhibiting androgen signalling. However, prostate tumours can evade such hormonal therapies in a number of different ways and therapy resistant disease, so-called castration-resistant prostate cancer (CRPC) is the major clinical problem. Somewhat counterintuitively, the androgen receptor remains a key therapy target in CRPC. Here, we explain why this is the case and summarise both new hormone therapy strategies and the recent advances in knowledge of androgen receptor structure and function that underpin them. Prostate cancer (PCa) is the most common cancer in men in the West, other than skin cancer, accounting for over a quarter of cancer diagnoses in US men. In a seminal paper from 1941, Huggins and Hodges demonstrated that prostate tumours and metastatic disease were sensitive to the presence or absence of androgenic hormones. The first hormonal therapy for PCa was thus castration. In the subsequent eighty years, targeting the androgen signalling axis, where possible using drugs rather than surgery, has been a mainstay in the treatment of advanced and metastatic disease. Androgens signal via the androgen receptor, a ligand-activated transcription factor, which is the direct target of many such drugs. In this review we discuss the role of the androgen receptor in PCa and how the combination of structural information and functional screenings is continuing to be used for the discovery of new drug to switch off the receptor or modify its function in cancer cells.
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