Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program

Hernan Carol, Christopher L. Morton, Richard Gorlick, E. Anders Kolb, Stephen T. Keir, C. Patrick Reynolds, Min H. Kang, John M. Maris, Catherine Billups, Malcolm A. Smith, Peter J. Houghton, Richard B. Lock

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Background: GSK690693 is a small molecule ATP-competitive inhibitor of the pro-survival kinase Akt. Since Akt regulates multiple downstream targets including transcription factors, glycogen synthase 3, the pro-apoptotic protein Bad, as well as MDM2 and mTORC1, it was tested against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Procedures: GSK690693 was tested in vitro at concentrations from 1nM to 10μM, and against the in vivo panel of xenografts at a dose of 30mg/kg daily×5 for 6 consecutive weeks. Three measures of in vivo antitumor activity were used: (1) an objective response measure modeled after the clinical setting; (2) a treated to control (T/C) tumor volume measure; and (3) a time to event measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Results: GSK690693 inhibited cell growth in vitro with IC 50 values between 6.5nM and >10μM. In vivo, GSK690693 significantly increased EFS in 11 of 34 (32%) solid tumor xenografts, most notably in all 6 osteosarcoma models, but not in any of the 8 ALL xenografts tested. No objective responses were observed and only one solid tumor met EFS T/C criteria for intermediate activity. Conclusions: GSK690693 demonstrated broad activity in vitro, however our results against both the solid tumor and ALL PPTP in vivo panels demonstrate that, as single agent at the dose and schedule used, GSK690693 has only modest antitumor activity.

Original languageEnglish (US)
Pages (from-to)1329-1337
Number of pages9
JournalPediatric Blood and Cancer
Volume55
Issue number7
DOIs
StatePublished - Dec 2010

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Pediatrics
Heterografts
Disease-Free Survival
Glycogen Synthase
Neoplasms
Apoptosis Regulatory Proteins
Osteosarcoma
Tumor Burden
GSK690693
Appointments and Schedules
Transcription Factors
Phosphotransferases
Adenosine Triphosphate
In Vitro Techniques
Growth

Keywords

  • Akt inhibitor
  • Developmental therapeutics
  • Preclinical testing

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Carol, H., Morton, C. L., Gorlick, R., Kolb, E. A., Keir, S. T., Reynolds, C. P., ... Lock, R. B. (2010). Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 55(7), 1329-1337. https://doi.org/10.1002/pbc.22710

Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. / Carol, Hernan; Morton, Christopher L.; Gorlick, Richard; Kolb, E. Anders; Keir, Stephen T.; Reynolds, C. Patrick; Kang, Min H.; Maris, John M.; Billups, Catherine; Smith, Malcolm A.; Houghton, Peter J.; Lock, Richard B.

In: Pediatric Blood and Cancer, Vol. 55, No. 7, 12.2010, p. 1329-1337.

Research output: Contribution to journalArticle

Carol, H, Morton, CL, Gorlick, R, Kolb, EA, Keir, ST, Reynolds, CP, Kang, MH, Maris, JM, Billups, C, Smith, MA, Houghton, PJ & Lock, RB 2010, 'Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 55, no. 7, pp. 1329-1337. https://doi.org/10.1002/pbc.22710
Carol, Hernan ; Morton, Christopher L. ; Gorlick, Richard ; Kolb, E. Anders ; Keir, Stephen T. ; Reynolds, C. Patrick ; Kang, Min H. ; Maris, John M. ; Billups, Catherine ; Smith, Malcolm A. ; Houghton, Peter J. ; Lock, Richard B. / Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2010 ; Vol. 55, No. 7. pp. 1329-1337.
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AU - Morton, Christopher L.

AU - Gorlick, Richard

AU - Kolb, E. Anders

AU - Keir, Stephen T.

AU - Reynolds, C. Patrick

AU - Kang, Min H.

AU - Maris, John M.

AU - Billups, Catherine

AU - Smith, Malcolm A.

AU - Houghton, Peter J.

AU - Lock, Richard B.

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