The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer.
The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer.
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DOI：
10.1016/j.cbi.2014.12.012
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发表时间：
2015-06-05
影响因子：
5.1
通讯作者：
Penning, Trevor M.
中科院分区：
文献类型：
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作者：
Tamae, Daniel;Mostaghel, Elahe;Montgomery, Bruce;Nelson, Peter S.;Balk, Steven P.;Kantoff, Philip W.;Taplin, Mary-Ellen;Penning, Trevor M.
前列腺癌是美国癌症死亡的第二大原因。局部高危疾病和新发转移性疾病的治疗经常导致复发。这些转移性去势抵抗性前列腺癌（mCRPC）的死亡率很高，尽管不断增长的雄激素剥夺、放射和免疫疗法的治疗手段可以延长患者的生存期。在这里，我们回顾了前列腺切除术前高危局限性前列腺癌新辅助治疗的两项研究，即总雄激素途径抑制（TAPS）试验和新辅助醋酸阿比特龙（AA）试验。这两项试验评估了非特异性 P450c17 抑制剂酮康唑和特异性 P450c17 抑制剂 AA 抑制组织和血清雄激素水平的功效。此外，在这些试验过程中，使用一种新颖且经过验证的稳定同位素稀释液相色谱电喷雾电离选择反应监测质谱分析来准确定量循环中的肾上腺和性腺雄激素。与未接受酮康唑或 AA 治疗的患者相比，接受酮康唑或 AA 治疗的患者的肾上腺雄激素、Δ4-雄烯-3,17-二酮、脱氢表雄酮和硫酸脱氢表雄酮显着降低。然而，在这两项试验中，大量的 DHEA-S (~20 μg/dL) 持续存在，因此可以作为瘤内转化为强效雄激素受体配体、睾酮 (T) 和 5α-二氢睾酮 (DHT) 的储存库。 Δ4-雄烯-3,17-二酮和 5α-雄烷二酮分别转化为 T 和 DHT 的最后一步由 AKR1C3 催化。因此，我们认为在 DHEA-S 储库的背景下，P450c17 和 AKR1C3 抑制可能是一种有效的组合治疗策略。
Prostate cancer is the second leading cause of cancer death in the United States. Treatment of localized high-risk disease and de novo metastatic disease frequently leads to relapse. These metastatic castration resistant prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of androgen deprivation, radiation and immunotherapies. Here, we review two studies of neoadjuvant treatment of high-risk localized prostate cancer prior to prostatectomy, the total androgen pathway suppression (TAPS) trial and the neoadjuvant abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor, ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum androgen levels. Furthermore, a novel and validated stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal androgens in circulation during the course of these trials. The adrenal androgens, Δ4-androstene-3,17-dione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly reduced in the patients receiving ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of DHEA-S (~20 μg/dL) persists and thus may serve as a depot for intratumoral conversion to the potent androgen receptor ligands, testosterone (T) and 5α-dihydrotestosterone (DHT). The final step in conversion of Δ4-androstene-3,17-dione and 5α-androstanedione to T and DHT, respectively, is catalyzed by AKR1C3. We therefore present the case that in the context of the DHEA-S depot, P450c17 and AKR1C3 inhibition may be an effective combinatorial treatment strategy.
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影响因子：
7.3
作者：
Liedtke, Andy J.;Adeniji, Adegoke O.;Chen, Mo;Byrns, Michael C.;Jin, Yi;Christianson, David W.;Marnett, Lawrence J.;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
影响因子：
64.5
作者：
Chang KH;Li R;Kuri B;Lotan Y;Roehrborn CG;Liu J;Vessella R;Nelson PS;Kapur P;Guo X;Mirzaei H;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
11.2
作者：
Hofland, Johannes;van Weerden, Wytske M.;de Jong, Frank H.
通讯作者：
de Jong, Frank H.
影响因子：
7.3
作者：
Adeniji, Adegoke O.;Twenter, Barry M.;Byrns, Michael C.;Jin, Yi;Chen, Mo;Winkler, Jeffrey D.;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
影响因子：
8.8
作者：
通讯作者：
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