A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer.
OBJECTIVE
Given discrepancies between preclinical and clinical observations of mammalian target of rapamycin (mTOR) inhibition in prostate cancer, we sought to determine the pharmacodynamic effects of the mTOR/TORC1 inhibitor rapamycin in men with intermediate- to high-risk prostate cancer undergoing radical prostatectomy.


METHODS
Rapamycin was given at 3 or 6 mg orally for 14 days before radical prostatectomy in men with multifocal Gleason sum > or =7 prostate cancer; 10 untreated control subjects were included. The primary outcome was inhibition of phosphorylation of ribosomal S6 in posttreatment radical prostatectomy versus pretreatment biopsy tumor tissue, evaluated using a Simon two-stage design for pharmacodynamic efficacy.


RESULTS
Thirty-two subjects were accrued: 20 at 3 mg, 2 at 6 mg, and 10 controls. No dose-limiting toxicities were observed at 3 mg; however, two of two men enrolled at 6 mg experienced dose-limiting toxicities including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg included stomatitis, rash, ileus, and neutropenia. Pharmacodynamic studies showed tumor S6 phosphorylation inhibition in 50% of 10 evaluable rapamycin-treated men with sufficient paired tissue [median 58% inhibition (P = 0.049) versus 2% inhibition in controls (P = 0.75)] with no significant effect on AKT activity. We observed no change in Ki-67 or caspase-3 cleavage but noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin treatment. Prostate tissue rapamycin concentrations were 3- to 4-fold higher than blood.


CONCLUSIONS
At 3 mg daily, rapamycin successfully and safely inhibited prostate cancer S6 phosphorylation and achieved relatively high prostate tissue concentrations. No effect on AKT phosphorylation, tumor proliferation, or apoptosis was observed.
Armstrong
Andrew J
AJ
Duke Comprehensive Cancer Center and Duke Prostate Center, Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina 27710, USA. andrew.armstrong@duke.edu
Netto
George J
GJ
Rudek
Michelle A
MA
Halabi
Susan
S
Wood
David P
DP
Creel
Patricia A
PA
Mundy
Kelly
K
Davis
S Lindsay
SL
Wang
Ting
T
Albadine
Roula
R
Schultz
Luciana
L
Partin
Alan W
AW
Jimeno
Antonio
A
Fedor
Helen
H
Febbo
Phillip G
PG
George
Daniel J
DJ
Gurganus
Robin
R
De Marzo
Angelo M
AM
Carducci
Michael A
MA
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D004334:Drug Administration Schedule; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010766:Phosphorylation; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus