Prostate cancer is an ideal target for chemoprevention.
To date, chemoprevention clinical trials with 5α-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.
Written by:
Jia S, Gao X, Lee SH, Maira SM, Wu X, Stack EC, Signoretti S, Loda M, Zhao JJ, Roberts TM. Are you the author?
Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute; Departments of Biological Chemistry and Molecular Pharmacology and Pathology, Harvard Medical School, Boston, Massachusetts; and Novartis Institutes for BioMedical Research, Inc., Oncology Disease Area, Basel, Switzerland.
Reference: Cancer Discov. 2012 Dec 28. Epub ahead of print.
doi: 10.1158/2159-8290.CD-12-0262
PubMed Abstract
PMID: 23258246
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