Ano de Publicação: 2010
AUTORIA
Andrew J. Armstrong, MD ScM1,†, George J. Netto, MD2, Michelle A Rudek, PharmD PhD2,
Susan Halabi, PhD1,3, David Wood, MD4, Patricia Creel, RN1, Kelly Mundy1, S. Lindsay
Davis5, Ting Wang, MS MHS2, Roula Albadine, MD2, Luciana Schultz, MD2, Alan Partin,
MD PhD2, Antonio Jimeno, MD PhD5, Helen Fedor2, Phillip G. Febbo, MD1, Daniel J.
George, MD1, Robin Gurganus, RN2, Angelo M. De Marzo, MD PhD2, and Michael A.
Carducci, MD2
1Duke Comprehensive Cancer Center and the Duke Prostate Center, Duke University, Durham,
NC
2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine Baltimore,
MD 21231
3Department of Biostatistics and Bioinformatics, Duke University, Durham NC
4University of Michigan, Ann Arbor, MI; Duke University, Durham, NC
5University of Colorado Cancer Center, Aurora, CO
RESUMO
Purpose—Given discrepancies between preclinical and clinical observations of mTOR inhibition in prostate cancer (PC), we sought to determine the pharmacodynamic (PD) effects of the mTOR inhibitor rapamycin in men with intermediate-high risk PC undergoing radical prostatectomy (RP). Experimental Design—Rapamycin was given at 3 or 6 mg orally for 14 days prior to RP in men with multifocal Gleason ≥7 PC; 10 untreated control subjects were included. The primary outcome was inhibition of phosphorylation of ribosomal S6 in post-treatment RP vs. pre-treatment biopsy tumor tissue, evaluated using a Simon 2-stage design for PD efficacy. Results—Thirty-two subjects were accrued, 20 at 3 mg, 2 at 6 mg, 10 controls. No dose-limiting toxicities (DLTs) were observed at 3 mg; however, 2/2 men enrolled at 6 mg experienced DLTs including thrombocytopenia and fever with grade 3 stomatitis. Adverse events observed at 3 mg included stomatitis, rash, ileus, and neutropenia. PD studies demonstrated tumor S6 phosphorylation inhibition in 50% of 10 evaluable rapamycin treated men with sufficient paired tissue (median 58% decline, p=0.049 vs. 2% decline in controls, p=0.75) with no significant effect on AKT activity. There was no change in Ki-67 or caspase-3 cleavage but we noted a reduction in cytoplasmic p27 staining with increased nuclear localization with rapamycin. Prostate tissue rapamycin concentrations were 3–4 fold higher than blood.