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Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention

Shidong, JIa, Massimo, Loda and Thomas, Roberts (2013) Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discovery, 3 (1). pp. 44-51. ISSN 2159-8274


Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5a-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 lossinduced 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. © 2012 American Association for Cancer Research.

Item Type: Article
Additional Information: This is a revision of a manuscript previously released back in April 2011 under OAK ID#4604.
Date Deposited: 29 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46