Akamatsu Shusuke, Inoue Takahiro, Ogawa Osamu, Gleave Martin E
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
Int J Urol. 2018 Apr;25(4):345-351. doi: 10.1111/iju.13526. Epub 2018 Feb 3.
Treatment-related neuroendocrine prostate cancer is a lethal form of prostate cancer that emerges in the later stages of castration-resistant prostate cancer treatment. Treatment-related neuroendocrine prostate cancer transdifferentiates from adenocarcinoma as an adaptive response to androgen receptor pathway inhibition. The incidence of treatment-related neuroendocrine prostate cancer has been rising due to the increasing use of potent androgen receptor pathway inhibitors. Typically, treatment-related neuroendocrine prostate cancer is characterized by either low or absent androgen receptor expression, small cell carcinoma morphology and expression of neuroendocrine markers. Clinically, it manifests with predominantly visceral or lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels or a short response duration to androgen deprivation therapy. Furthermore, although the tumor initially responds to platinum-based chemotherapy, the duration of the response is short. Based on the poor prognosis, it is imperative to identify novel molecular targets for treatment-related neuroendocrine prostate cancer. Recent advances in genomic and molecular research, supported by novel in vivo models, have identified some of the key molecular characteristics of treatment-related neuroendocrine prostate cancer. The gain of MYCN and AURKA oncogenes, along with the loss of tumor suppressor genes TP53 and RB1 are key genomic alterations associated with treatment-related neuroendocrine prostate cancer. Androgen receptor repressed genes, such as BRN2 and PEG10, are also necessary for treatment-related neuroendocrine prostate cancer. These genetic changes converge on pathways upregulating genes, such as SOX2 and EZH2, that facilitate lineage plasticity and neuroendocrine differentiation. As a result, on potent androgen receptor pathway inhibition, castration-resistant prostate cancer transdifferentiates to treatment-related neuroendocrine prostate cancer in a clonally divergent manner. Further understanding of the disease biology is required to develop novel drugs and biomarkers that would help treat this aggressive prostate cancer variant.
治疗相关的神经内分泌前列腺癌是前列腺癌的一种致命形式，出现在去势抵抗性前列腺癌治疗的后期。治疗相关的神经内分泌前列腺癌由腺癌转分化而来，是对雄激素受体通路抑制的一种适应性反应。由于强效雄激素受体通路抑制剂的使用增加，治疗相关的神经内分泌前列腺癌的发病率一直在上升。通常，治疗相关的神经内分泌前列腺癌的特征是雄激素受体表达低或缺失、小细胞癌形态以及神经内分泌标志物的表达。临床上，它主要表现为内脏或溶骨性骨转移、巨大肿瘤肿块、低前列腺特异性抗原水平或对雄激素剥夺治疗的反应持续时间短。此外，尽管肿瘤最初对铂类化疗有反应，但反应持续时间很短。基于预后不良，必须为治疗相关的神经内分泌前列腺癌确定新的分子靶点。在新型体内模型的支持下，基因组和分子研究的最新进展已经确定了治疗相关的神经内分泌前列腺癌的一些关键分子特征。MYCN和AURKA癌基因的获得，以及肿瘤抑制基因TP53和RB1的缺失是与治疗相关的神经内分泌前列腺癌相关的关键基因组改变。雄激素受体抑制基因，如BRN2和PEG10，对于治疗相关的神经内分泌前列腺癌也是必需的。这些基因变化汇聚在上调基因的通路上，如SOX2和EZH2，这些通路促进谱系可塑性和神经内分泌分化。因此，在强效雄激素受体通路抑制下，去势抵抗性前列腺癌以克隆性分化的方式转分化为治疗相关的神经内分泌前列腺癌。需要进一步了解疾病生物学，以开发有助于治疗这种侵袭性前列腺癌变体的新型药物和生物标志物。
