Purpose: 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.Experimental Design: Rapamycin was given at 3 or 6 mg orally for 14 days before radical prostatectomy in men with multifocal Gleason sum ≥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. Clin Cancer Res; 16(11); 3057-66. ©2010 AACR.Although rapamycin analogues have provided benefit to patients with advanced renal cell carcinoma, the effect of mammalian target of rapamycin (mTOR) inhibition in other solid tumors, including prostate cancer, remains unclear (1-3). The rationale for mTOR inhibition is strong in advanced prostate cancer, given the high prevalence of activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway due largely to the loss of expression/function of the tumor suppressor PTEN and the association of this pathway with adverse pathologic features, recurrence after radical prostatectomy, and systemic treatment resistance (4-8). Preclinical studies have shown an ability of TORC1 inhibitors to revert prostatic intraepithelial neoplasia and reduce tumor volume and growth/proliferation particularly in tumors with activated AKT or that lack PTEN (9-12). Thus, preclinical studies support the development of mTOR inhibitors in prostate cancer (11,(13)(14)(15).The clinical experience of TORC1 inhibition with rapamycin analogues in men with castrate-resistant prostate cancer, however, has been disappointing with few responses and a short time to progression ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.