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

Abstract

UNLABELLED:

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.

SIGNIFICANCE:

Chemoprevention with antiandrogen therapies is attractive for prostate cancer, given its prevalence and established hormonally mediated pathogenesis. However, because PTEN loss has been found in 9% to 45% of HG-PIN in the clinic, the current findings suggest that patients with PTEN-deficient prostate tumors might be better treated with PI3K-targeted therapies.

• Authors: Shidong Jia, Xueliang Gao, Sang Hyun Lee, Sauveur-Michel Maira, Xiaoqiu Wu, Edward C Stack, Sabina Signoretti, Massimo Loda, Jean J Zhao, Thomas M Roberts
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 1 Pg. 44-51 (Jan 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23258246 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AZD 6244
• Aminopyridines
• Androgen Receptor Antagonists
• Antineoplastic Agents
• Benzamides
• Benzimidazoles
• Imidazoles
• Morpholines
• NVP-BKM120
• Nitriles
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Quinolines
• Phenylthiohydantoin
• Testosterone
• enzalutamide
• MAP Kinase Kinase Kinases
• PTEN Phosphohydrolase
• Pten protein, mouse
• dactolisib

Topics

• Aminopyridines (therapeutic use)
• Androgen Receptor Antagonists (therapeutic use)
• Animals
• Antineoplastic Agents (therapeutic use)
• Benzamides
• Benzimidazoles (therapeutic use)
• Castration
• Imidazoles (therapeutic use)
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Male
• Mice
• Mice, Transgenic
• Morpholines (therapeutic use)
• Nitriles
• PTEN Phosphohydrolase (genetics)
• Phenylthiohydantoin (analogs & derivatives, therapeutic use)
• Phosphatidylinositol 3-Kinases (genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Prostatic Intraepithelial Neoplasia (metabolism, pathology, prevention & control)
• Prostatic Neoplasms (metabolism, pathology, prevention & control)
• Protein Kinase Inhibitors (therapeutic use)
• Quinolines (therapeutic use)
• Testosterone (metabolism)