title: Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention.
abstract: 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Shidong
authors.initials: S
authors.lastname: Jia
authors.forename: Xueliang
authors.initials: X
authors.lastname: Gao
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
authors.forename: Xiaoqiu
authors.initials: X
authors.lastname: Wu
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Roberts
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001562:Benzimidazoles / Q000627:therapeutic use; D002369:Castration; D007093:Imidazoles / Q000627:therapeutic use; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000627:therapeutic use; D009570:Nitriles; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use; D013739:Testosterone / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D001562:Benzimidazoles; D007093:Imidazoles; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D009570:Nitriles; D051059:PTEN Phosphohydrolase; D010669:Phenylthiohydantoin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D013739:Testosterone; C517975:AZD 6244; C571178:NVP-BKM120; C540278:enzalutamide; C487757:Pten protein, mouse; C531198:dactolisib