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Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program.

Publication ,  Journal Article
Houghton, PJ; Morton, CL; Kolb, EA; Gorlick, R; Lock, R; Carol, H; Reynolds, CP; Maris, JM; Keir, ST; Billups, CA; Smith, MA
Published in: Pediatr Blood Cancer
April 2008

BACKGROUND: Rapamycin is a highly specific inhibitor of mTOR, a serine/threonine kinase that controls cap-dependent translation. Here we report the activity of rapamycin against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). PROCEDURES: Rapamycin was tested against the in vitro panel at concentrations from 0.01 to 100 nM and was tested against the in vivo tumor panels by i.p. administration daily x 5 for 6 consecutive weeks at a dose of 5 mg/kg. RESULTS: Rapamycin variably inhibited growth of the cell lines in the PPTP in vitro panel, with maximal inhibition values ranging from 19% to 85% (median 49%) and a median EC(50) of 0.7 nM. Ten of 23 cell lines achieved at least 50% growth inhibition. Against the in vivo panels, rapamycin induced significant differences in EFS distribution in 27 of 36 solid tumor xenografts and in 5 of 8 ALL xenografts. Using the time to event activity measure, rapamycin had intermediate or high activity against 14 of 31 evaluable solid tumor xenografts and 5 of 8 ALL xenografts. Objective responses were observed in several panels, including: rhabdoid tumor (1PR), rhabdomyosarcoma (2PR), and osteosarcoma (1 maintained CR). Two T-cell ALL xenografts had objective responses (1PR, 1 maintained CR). CONCLUSIONS: Rapamycin demonstrated broad antitumor activity against the PPTP's in vivo tumor panels, with particularly noteworthy activity for selected sarcoma and ALL xenografts. Future work will evaluate the molecular characteristics of responding models and the activity of combinations of rapamycin with other anticancer agents.

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Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

April 2008

Volume

50

Issue

4

Start / End Page

799 / 805

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sirolimus
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Mice
  • Humans
  • Female
  • Cell Proliferation
  • Cell Line, Tumor
  • Antibiotics, Antineoplastic
 

Citation

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Houghton, P. J., Morton, C. L., Kolb, E. A., Gorlick, R., Lock, R., Carol, H., … Smith, M. A. (2008). Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer, 50(4), 799–805. https://doi.org/10.1002/pbc.21296
Houghton, Peter J., Christopher L. Morton, E Anders Kolb, Richard Gorlick, Richard Lock, Hernan Carol, C Patrick Reynolds, et al. “Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program.Pediatr Blood Cancer 50, no. 4 (April 2008): 799–805. https://doi.org/10.1002/pbc.21296.
Houghton PJ, Morton CL, Kolb EA, Gorlick R, Lock R, Carol H, et al. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Apr;50(4):799–805.
Houghton, Peter J., et al. “Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program.Pediatr Blood Cancer, vol. 50, no. 4, Apr. 2008, pp. 799–805. Pubmed, doi:10.1002/pbc.21296.
Houghton PJ, Morton CL, Kolb EA, Gorlick R, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA. Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer. 2008 Apr;50(4):799–805.
Journal cover image

Published In

Pediatr Blood Cancer

DOI

EISSN

1545-5017

Publication Date

April 2008

Volume

50

Issue

4

Start / End Page

799 / 805

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Sirolimus
  • Oncology & Carcinogenesis
  • Neoplasms, Experimental
  • Mice
  • Humans
  • Female
  • Cell Proliferation
  • Cell Line, Tumor
  • Antibiotics, Antineoplastic