Opposing Effects of Androgen Deprivation and Targeted Therapy on Prostate Cancer Prevention

被引：45

作者：

Jia, Shidong ^{[1
,4
]}

Gao, Xueliang ^{[1
,3
]}

Lee, Sang Hyun ^{[1
,4
]}

Maira, Sauveur-Michel ^{[5
]}

Wu, Xiaoqiu ^{[2
,4
]}

Stack, Edward C. ^{[2
,4
]}

Signoretti, Sabina ^{[2
,4
]}

Loda, Massimo ^{[2
,4
]}

Zhao, Jean J. ^{[1
,3
]}

Roberts, Thomas M. ^{[1
,3
]}

机构：

[1] Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[5] Novartis Inst BioMed Res Inc, Oncol Dis Area, Basel, Switzerland

来源：

CANCER DISCOVERY | 2013年 / 3卷 / 01期

关键词：

INTRAEPITHELIAL NEOPLASIA; PTEN; CELL; EXPRESSION; DELETION; GENE; PI3K;

D O I：

10.1158/2159-8290.CD-12-0262

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5 alpha-reductase inhibitors have yielded encouraging yet ultimately confounding results. Using a preclinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, in which surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to invasive castration-resistant prostate cancer (CRPC). As an alternative, targeting the phosphoinositide 3-kinase (PI3K) signaling pathway via either genetic ablation of genes encoding PI3K components or pharmacologic inhibition of the PI3K pathway reversed the PTEN loss-induced HG-PIN phenotype. Finally, concurrent inhibition of the PI3K and mitogen-activated protein kinase (MAPK) pathways was effective in blocking the growth of PTEN-null CRPC. Together, these data have revealed the potential adverse effects of antiandrogen chemoprevention in certain genetic contexts (such as PTEN loss) while showing the promise of targeted therapy in the clinical management of this complex and prevalent disease.

引用

页码：44 / 51

页数：8

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