Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR.
BACKGROUND
To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models.


METHODS
Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment.


RESULTS
The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle-treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model.


CONCLUSIONS
This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment.
Schayowitz
A
A
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Health Science Facility I, Room 580G, 685 West Baltimore Street, Baltimore, MD 21201, USA.
Sabnis
G
G
Goloubeva
O
O
Njar
V C O
VC
Brodie
A M H
AM
D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000730:Androstadienes / Q000008:administration & dosage*; D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D002369:Castration; D045744:Cell Line, Tumor; D018450:Disease Progression; D004359:Drug Therapy, Combination; D000068338:Everolimus; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D009570:Nitriles / Q000008:administration & dosage*; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D020239:Receptor Cross-Talk; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases; D014105:Tosyl Compounds / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000730:Androstadienes; D000813:Anilides; D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; D009570:Nitriles; D014105:Tosyl Compounds; D000068338:Everolimus; C053541:bicalutamide; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D017430:Prostate-Specific Antigen; D020123:Sirolimus; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene