Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.
Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.
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DOI：
10.1016/j.eururo.2016.03.049
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发表时间：
2016-10
期刊：
影响因子：
23.4
通讯作者：
Plymate, Stephen R.
中科院分区：
文献类型：
--
作者：
Welti, Jonathan;Rodrigues, Daniel Nava;Sharp, Adam;Sun, Shihua;Lorente, David;Riisnaes, Ruth;Figueiredo, Ines;Zafeiriou, Zafeiris;Rescigno, Pasquale;de Bono, Johann S.;Plymate, Stephen R.
关键词：
雄激素受体剪接变异体-7(AR-V7)与去势抵抗型前列腺癌(CRPC)的发生以及对阿比特龙和苯扎鲁胺的耐药有关。目的建立一种检测肿瘤组织中AR-V7蛋白的方法，并探讨其在激素敏感型前列腺癌(HSPC)向慢性前列腺癌进展过程中的表达及其临床意义。在产生和验证单抗后，我们回顾鉴定了可用于AR-V7免疫组化(IHC)分析的HSPC和CRPC组织的患者。用IHC H评分(HS)数据检测AR-V7的核表达。检测从HSPC到CRPC的AR-V7核表达的变化，以及AR-V7核表达与总生存期的关系。与CRPC(HS135，IQR80-157.5；P<；0.0001)相比，HSPC(中位数HS50，四分位数范围17.5-90)和活检组织(HS80，IQR30-136.3)的核AR-V7表达显著降低(HS140，IQR105-167.5；P=0.007)阿比特龙或苯扎鲁胺治疗后。CRPC活检组织中AR-V7的低表达与较长的OS相关(风险比1.012，95%可信区间1.004-1.020；p=0.003)。虽然这种单抗主要与PC活检组织中的AR-V7结合，但它也可能与其他蛋白质结合。我们提供了第一个证据，即核AR-V7的表达随着CRPC的出现而增加，并且与AR N-末端区域的抗体染色不同，它可以预测OS的预后。这些数据表明，AR-V7在CRPC疾病生物学中很重要；需要针对AR剪接变体的药物来验证这一假说，并进一步改善CRPC的患者预后。在这项研究中，我们发现晚期前列腺癌患者AR-V7蛋白水平较高。AR-V7水平较高的患者对某些前列腺癌治疗反应较差，生存时间较短。雄激素受体剪接变异体7(AR-V7)的表达随着去势抵抗的增加而增加，在阿比特龙或苯扎鲁胺治疗后进一步增加，并与转移性去势抵抗前列腺癌的不良预后相关，不同于总的AR表达，提示在治疗抵抗中起作用。需要针对AR-V7的药物来验证这一假设。
The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5–90) compared to CRPC (HS 135, IQR 80–157.5; p < 0.0001), and in biopsy tissue taken before (HS 80, IQR 30–136.3) compared to after (HS 140, IQR 105–167.5; p = 0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004–1.020; p = 0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. Androgen receptor splice variant-7 (AR-V7) expression increases with castration resistance and further increases following abiraterone or enzalutamide treatment, and is associated with worse outcome for metastatic castration-resistant prostate cancer, unlike total AR expression, suggesting a role in treatment resistance. Agents targeting AR-V7 are needed to test this hypothesis.
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影响因子：
8.8
作者：
Bianchini, D.;Omlin, A.;Pezaro, C.;Lorente, D.;Ferraldeschi, R.;Mukherji, D.;Crespo, M.;Figueiredo, I.;Miranda, S.;Riisnaes, R.;Zivi, A.;Buchbinder, A.;Rathkopf, D. E.;Attard, G.;Scher, H. I.;de Bono, J.;Danila, D. C.
通讯作者：
Danila, D. C.
影响因子：
158.5
作者：
Scher, Howard I.;Fizazi, Karim;de Bono, Johann S.
通讯作者：
de Bono, Johann S.
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
4.6
作者：
Qu Y;Dai B;Ye D;Kong Y;Chang K;Jia Z;Yang X;Zhang H;Zhu Y;Shi G
通讯作者：
Shi G
影响因子：
23.4
作者：
Efstathiou, Eleni;Titus, Mark;Wen, Sijin;Hoang, Anh;Karlou, Maria;Ashe, Robynne;Tu, Shi Ming;Aparicio, Ana;Troncoso, Patricia;Mohler, James;Logothetis, Christopher J.
通讯作者：
Logothetis, Christopher J.