title: A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer.
abstract: 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.
authors.affiliation: Duke Comprehensive Cancer Center and Duke Prostate Center, Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina 27710, USA. andrew.armstrong@duke.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Susan
authors.initials: S
authors.lastname: Halabi
authors.forename: David P
authors.initials: DP
authors.lastname: Wood
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Creel
authors.forename: Kelly
authors.initials: K
authors.lastname: Mundy
authors.forename: S Lindsay
authors.initials: SL
authors.lastname: Davis
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Roula
authors.initials: R
authors.lastname: Albadine
authors.forename: Luciana
authors.initials: L
authors.lastname: Schultz
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Helen
authors.initials: H
authors.lastname: Fedor
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Febbo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
authors.forename: Robin
authors.initials: R
authors.lastname: Gurganus
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
mesh_terms: 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
chemical_list: 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