Dhavale Meera, Abdelaal Mohamed K, Alam A B M Nasibul, Blazin Tatjana, Mohammed Linha M, Prajapati Dhruvil, Ballestas Natalia P, Mostafa Jihan A
Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.
Cureus. 2021 Feb 17;13(2):e13402. doi: 10.7759/cureus.13402.
Androgen receptor signaling primarily influences both the normal growth and proliferation of the prostate gland and the development of prostatic carcinoma. While localized prostate cancers are typically managed with definitive therapies like surgery and radiotherapy, many patients have recurrences in the form of metastatic disease. Androgen deprivation therapy, by way of castration via orchiectomy or with drugs like luteinizing hormone-releasing hormone (commonly called gonadotropin-releasing hormone) agonists and luteinizing hormone-releasing hormone antagonists, is the primary mode of therapy for advanced castration-sensitive prostate cancer. Castration resistance invariably develops in these patients. Further treatment has shifted to newer anti-androgen drugs like enzalutamide or abiraterone and taxane-based chemotherapy. Prolonged inhibition of the androgen receptor signaling pathway causes androgen receptor-independent clonal evolution which leads to the development of treatment-emergent neuroendocrine prostate cancer. All prostate cancers at the initial presentation should undergo evaluation for the markers of neuroendocrine differentiation. Detection of serum biomarkers of neuroendocrine differentiation and circulating tumor cells is a prospective non-invasive method of detecting neuroendocrine transdifferentiation in patients undergoing treatment with androgen receptor pathway inhibitors. It is essential to perform a biopsy in the presence of red flags of neuroendocrine differentiation. Alisertib, an Aurora kinase inhibitor, showed promising clinical benefit in a subgroup of patients with certain molecular alterations. A thorough understanding of the molecular and clinical programming of treatment-emergent neuroendocrine prostate cancer can potentially lead to the development of drugs to prevent the development of this lethal variant of prostate cancer.
雄激素受体信号传导主要影响前列腺的正常生长和增殖以及前列腺癌的发展。虽然局限性前列腺癌通常采用手术和放疗等确定性疗法进行治疗，但许多患者会出现转移性疾病复发。通过睾丸切除术去势或使用促黄体生成素释放激素（通常称为促性腺激素释放激素）激动剂和促黄体生成素释放激素拮抗剂等药物进行雄激素剥夺治疗，是晚期去势敏感性前列腺癌的主要治疗方式。这些患者不可避免地会产生去势抵抗。进一步的治疗已转向新型抗雄激素药物，如恩杂鲁胺或阿比特龙以及紫杉烷类化疗。对雄激素受体信号通路的长期抑制会导致雄激素受体非依赖性克隆进化，从而导致治疗中出现的神经内分泌前列腺癌的发展。所有初诊的前列腺癌患者都应进行神经内分泌分化标志物的评估。检测神经内分泌分化的血清生物标志物和循环肿瘤细胞是一种前瞻性非侵入性方法，用于检测接受雄激素受体通路抑制剂治疗的患者中的神经内分泌转分化。在存在神经内分泌分化警示信号的情况下进行活检至关重要。阿利西替尼，一种极光激酶抑制剂，在具有某些分子改变的患者亚组中显示出有前景的临床益处。对治疗中出现的神经内分泌前列腺癌的分子和临床程序有透彻的了解可能会推动开发预防这种致命性前列腺癌变体发展的药物。
