Oncotarget：治疗耐药性前列腺癌的新型靶点

  近日，一篇发表在国际杂志Oncotarget上的研究论文中，来自帕克癌症研究所(Roswell Park Cancer Institute)的研究人员发现了一种可以控制恶性耐药性前列腺癌的新方法，文章中，研究者在对雄激素靶向疗法产生耐药性的前列腺癌中鉴别出了两个过表达的基因，雄激素靶向疗法即利用恩杂鲁胺和醋酸阿比特龙来进行前列腺癌的治疗。

  此前的研究发现，这两个名为Top2a和Ezh2的基因与恶性前列腺癌直接相关，而本文的研究者首次发现这两个基因处于过表达的状态；研究者Ellis说道，在对前列腺癌模型进行的两项独立临床前试验中，我们发现其对雄激素靶向疗法产生耐药性，同时也揭示了新型疗法对耐药性前列腺癌的治疗效果。

  本文的研究结果加深了研究人员对恶性前列腺癌病因的理解，研究者希望后期研究中可以寻找到更多的生物标记物和治疗靶点，同时他们也希望在其它癌症中发现基因Top2a和Ezh2的过表达状况，这就为后期寻找生物标记物来开发有效的靶向疗法提供了思路。

  最后研究者希望，本文进行的临床前试验结果可以为后期开发治疗患者机体的耐药性前列腺癌提供一定的思路和意见。（转化医学网360zhyx.com）

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转化医学网推荐的原文阅读：

TOP2A identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer
Oncotarget
Kevin Schaarschuch1, Jason Kirk1, Zafardjan Dalimov1, Elena Lasorsa1, Qiang Hu2, Swathi
Ramakrishnan1, ShengYu Ku1, Jianmin Wang2, Leigh Ellis
Prostate cancer (PCa) is the most diagnosed cancer and the second leading cause of cancer
death in men in the United States. With recent advances in treatments for advanced PCa,
sustainable suppression of disease still remains a primary challenge and new treatment
strategies are required. Increased use of high-throughput sequencing has resulted in more
defined molecular classification of PCa. Translation of these results into clinically relevant
biomarkers and/or therapeutic targets is essential for the successful evolution of precision
medicine in PCa. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a total of 254 differentially expressed genes in metastatic tumors compared to matched primary tumors. DAVID analysis indicated enrichments of GO terms related to chromosome function. Highlighted by these GO terms was the gene topoisomerase IIα, TOP2A(TOP2A). TOP2A mediates DNA topological structure and cell cycle progression and has been targeted for many years by chemotherapy agents, including the topoisomerase II (TOP2) inhibitor etoposide. Analysis of PCa clinical data sets through the cBioPortal for Cancer Genomics revealed that increased TOP2A in primary tumor samples identified patients with significantly worse disease free survival and was significantly increased in metastatic disease samples, as indicated by our mouse studies. Gene set enrichment analysis (GSEA) and spearman correlation of primary tumor samples with increased TOP2A showed significant positive correlation with the histone methyltransferase, EZH2. For this reason, we investigated the potential of combining the TOP2 inhibitor etoposide with the EZH2 inhibitor GSK126. To date, in vitro studies reveal that combination of non-cytotoxic concentrations of etoposide with GSK126 significantly increased cell death in two androgen sensitive adenocarcinoma cell lines (Myc-CaP and LnCaP) and the neuroendocrine androgen insensitive cell line, TRAMP C2. Further, cell death was associated with shut down of androgen receptor (AR) transcription, increased loss of EZH2 protein and histone H3 lysine 27 trimethylation. Current studies are ongoing to evaluate DNA damage and in vivo therapeutic efficacy. Overall, our studies suggest that patients screened for TOP2A and EZH2 expression could exhibit greater response to a combinational treatment involving low dose etoposide combined with EZH2 inhibition. Further, our data suggests that this combination therapeutic strategy can be beneficial independent of AR status, and provides rationale for continued clinical development.