Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.
Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.
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DOI：
10.1038/nature17954
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发表时间：
2016-05-26
期刊：
影响因子：
64.8
通讯作者：
Sharifi, Nima
中科院分区：
文献类型：
--
作者：
Li, Zhenfei;Alyamani, Mohammad;Li, Jianneng;Rogacki, Kevin;Abazeed, Mohamed;Upadhyay, Sunil K.;Balk, Steven P.;Taplin, Mary-Ellen;Auchus, Richard J.;Sharifi, Nima
阿比特龙阻断雄激素合成并延长去势抵抗性前列腺癌患者的生存期，否则这是由肿瘤内雄激素合成驱动的。阿比特龙在患者体内代谢为D4A， D4A具有更强的抗肿瘤活性，并且与内源性甾体5α-还原酶底物（如睾酮）具有结构相似性。在这里，我们发现D4A被转化为至少35个5α-还原和35个5β-还原的代谢物。最初的5α-还原代谢产物3-酮-5α-abi在服用阿比特龙的前列腺癌患者中比D4A更丰富，是一种雄激素受体（AR）激动剂，可促进前列腺癌的进展。在阿比特龙单独使用，随后阿比特龙加杜他雄胺（一种5α-还原酶抑制剂）的临床试验中，3-酮-5α-abi和下游代谢物被耗尽，而D4A浓度上升，有效地阻断了促肿瘤代谢物的产生，并允许D4A积累。此外，杜他雄胺不消耗3种5α-还原代谢物，这3种代谢物在临床上也可以检测到，这表明药理学上的5α-还原酶抑制对阿比特龙代谢具有特异性的生化作用。我们的发现提示了一种以前未被重视的生化特异性临床微调阿比特龙代谢的方法，以优化治疗。
Abiraterone blocks androgen synthesis and prolongs survival in castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to D4A, which has even greater anti-tumor activity and structural similarities to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least 3 5α-reduced and 3 5β-reduced metabolites. The initial 5α-reduced metabolite, 3-keto-5α-abi, is more abundant than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor (AR) agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abi and downstream metabolites are depleted, while D4A concentrations rise, effectively blocking production of a tumor-promoting metabolite and permitting D4A accumulation. Furthermore, dutasteride does not deplete three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacologic 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.
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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：
28.2
作者：
Miyamoto DT;Lee RJ;Stott SL;Ting DT;Wittner BS;Ulman M;Smas ME;Lord JB;Brannigan BW;Trautwein J;Bander NH;Wu CL;Sequist LV;Smith MR;Ramaswamy S;Toner M;Maheswaran S;Haber DA
通讯作者：
Haber DA
影响因子：
64.8
作者：
Li Z;Bishop AC;Alyamani M;Garcia JA;Dreicer R;Bunch D;Liu J;Upadhyay SK;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
11.2
作者：
Mohler, James L.;Titus, Mark A.;Wilson, Elizabeth M.
通讯作者：
Wilson, Elizabeth M.