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A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer.

Publication ,  Journal Article
Armstrong, AJ; Netto, GJ; Rudek, MA; Halabi, S; Wood, DP; Creel, PA; Mundy, K; Davis, SL; Wang, T; Albadine, R; Schultz, L; Partin, AW ...
Published in: Clin Cancer Res
June 1, 2010

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 > 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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

June 1, 2010

Volume

16

Issue

11

Start / End Page

3057 / 3066

Location

United States

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Ribosomal Protein S6 Kinases
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Prostatectomy
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Neoadjuvant Therapy
  • Middle Aged
 

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Armstrong, A. J., Netto, G. J., Rudek, M. A., Halabi, S., Wood, D. P., Creel, P. A., … Carducci, M. A. (2010). A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. Clin Cancer Res, 16(11), 3057–3066. https://doi.org/10.1158/1078-0432.CCR-10-0124
Armstrong, Andrew J., George J. Netto, Michelle A. Rudek, Susan Halabi, David P. Wood, Patricia A. Creel, Kelly Mundy, et al. “A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer.Clin Cancer Res 16, no. 11 (June 1, 2010): 3057–66. https://doi.org/10.1158/1078-0432.CCR-10-0124.
Armstrong AJ, Netto GJ, Rudek MA, Halabi S, Wood DP, Creel PA, et al. A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. Clin Cancer Res. 2010 Jun 1;16(11):3057–66.
Armstrong, Andrew J., et al. “A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer.Clin Cancer Res, vol. 16, no. 11, June 2010, pp. 3057–66. Pubmed, doi:10.1158/1078-0432.CCR-10-0124.
Armstrong AJ, Netto GJ, Rudek MA, Halabi S, Wood DP, Creel PA, Mundy K, Davis SL, Wang T, Albadine R, Schultz L, Partin AW, Jimeno A, Fedor H, Febbo PG, George DJ, Gurganus R, De Marzo AM, Carducci MA. A pharmacodynamic study of rapamycin in men with intermediate- to high-risk localized prostate cancer. Clin Cancer Res. 2010 Jun 1;16(11):3057–3066.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

June 1, 2010

Volume

16

Issue

11

Start / End Page

3057 / 3066

Location

United States

Related Subject Headings

  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Ribosomal Protein S6 Kinases
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Prostatectomy
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Neoadjuvant Therapy
  • Middle Aged