Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer.
Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer.
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DOI：
10.1016/j.eururo.2014.05.005
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发表时间：
2015-01
期刊：
影响因子：
23.4
通讯作者：
Logothetis, Christopher J.
中科院分区：
文献类型：
--
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.
关键词：
Enzalutamide是一种新型抗雄激素药物，已证实在转移性去势抵抗性前列腺癌（mCRPC）中具有疗效。评价Enzalutamide对癌症以及血液和骨髓中雄激素的影响，并将其与临床观察结果相关联。在这项前瞻性II期研究中，60例骨mCRPC患者接受了Enzalutamide 160 mg每日口服给药，并在治疗前和治疗第8周时进行了经髂骨骨髓活检。雄激素信号成分（雄激素受体[AR]、ARV 7、v-ets禽成红细胞增多症病毒E26癌基因同源物[ERG]、细胞色素P450、家族17、亚家族A、多肽1 [CYP 17]）和参与mCRPC进展的分子免疫组化检测磷酸化Met、磷酸化Src、糖皮质激素受体、Ki 67;睾酮、皮质醇和雄烯二酮浓度通过液相色谱-串联质谱法进行评估; AR拷贝数通过实时聚合酶链反应进行评估。采用描述性统计。至治疗中止的中位时间为22周（95%置信区间，19.9-29.6）。22例（37%）患者表现出对enzalutamide的原发性耐药，在4个月内停止治疗。分别有27例（45%）和13例（22%）患者的最大前列腺特异性抗原（PSA）下降≥50%和≥90%。治疗8周后，骨髓和循环睾酮水平升高。治疗前肿瘤细胞核AR过表达（>75%）和CYP 17表达（>10%）与获益相关（p = 0.018）。在23个可评价配对样本中的8个配对样本（PSA下降）中证实了AR亚细胞定位从细胞核的偏移。ARV 7变异体的存在与Enzalutamide的原发性耐药相关（p = 0.018）。有限的患者数量需要进一步验证。观察到的AR从细胞核的亚细胞转移和睾酮浓度升高提供了人类中Enzalutamide抑制AR信号传导同时诱导适应性反馈的第一个证据。mCRPC中持续的雄激素信号传导可预测获益，ARV 7与原发性耐药相关。我们报告了第一项在转移性前列腺癌中进行的骨活检研究，旨在寻找Enzalutamide治疗结局的预测因素。益处与治疗前雄激素信号传导特征相关。
Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC). To evaluate enzalutamide’s effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations. In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160 mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment. Androgen signaling components (androgen receptor [AR], ARV7, v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography–tandem mass spectrometry; and AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied. Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9–29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥50% and ≥90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (>75%) and CYP17 (>10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation. The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance. We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.
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DOI：
10.1097/med.0b013e3283381a31
发表时间：
2010-06
期刊：
Current opinion in endocrinology, diabetes, and obesity
影响因子：
--
作者：
Penning TM
通讯作者：
Penning TM
影响因子：
168.9
作者：
Scher, Howard I.;Beer, Tomasz M.;Higano, Celestia S.;Anand, Aseem;Taplin, Mary-Ellen;Efstathiou, Eleni;Rathkopf, Dana;Shelkey, Julia;Yu, Evan Y.;Alumkal, Joshi;Hung, David;Hirmand, Mohammad;Seely, Lynn;Morris, Michael J.;Danila, Daniel C.;Humm, John;Larson, Steve;Fleisher, Martin;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
DOI：
10.1158/1078-0432.ccr-13-1863
发表时间：
2014-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Yu Z;Chen S;Sowalsky AG;Voznesensky OS;Mostaghel EA;Nelson PS;Cai C;Balk SP
通讯作者：
Balk SP
影响因子：
45.3
作者：
Efstathiou, Eleni;Titus, Mark;Logothetis, Christopher J.
通讯作者：
Logothetis, Christopher J.
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.