Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background: MK-2206 is a small molecule allosteric inhibitor of Akt/PKB that is undergoing clinical trials for treatment of cancer. Procedures: MK-2206 was tested against the PPTP in vitro panel using a 96-hour exposure (1.0nM-10μM), and in vivo using thrice weekly dosing for a planned 4 weeks at its maximum tolerated dose (MTD) of 180mg/kg. Results: In vitro, the median relative IC 50 value for MK-2206 was 2.2μM. Four cell lines with IC 50 values<200nM included two ALL cell lines (COG-LL-317 and RS4;11), an AML cell line with an activating KIT mutation (Kasumi-1), and a Ewing sarcoma cell line (CHLA-10). In vivo, MK-2206 induced significant differences in EFS distribution compared to control in 12 of 29 (41%) of the evaluable solid tumor xenografts and in 2 of 8 (25%) of the evaluable ALL xenografts. Significant differences in EFS distribution were most frequently noted in the osteosarcoma panel (6 of 6). A single solid tumor xenograft (OS-31) had a greater than twofold increase in time to event compared to control animals, with all other solid tumor xenografts showing lesser degrees of tumor growth inhibition. Objective responses were not observed for either the solid tumor or ALL xenografts. Conclusions: MK-2206 showed its most consistent activity in vitro against ALL cell lines and in vivo against osteosarcoma xenografts. However, no objective responses were observed in solid tumor or ALL xenografts. Further preclinical work evaluating MK-2206 in pediatric models in the combination therapy setting may contribute to its pediatric development.

Original languageEnglish (US)
Pages (from-to)518-524
Number of pages7
JournalPediatric Blood and Cancer
Volume59
Issue number3
DOIs
StatePublished - Sep 2012

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Heterografts
Pediatrics
Cell Line
Neoplasms
Osteosarcoma
Ewing's Sarcoma
Maximum Tolerated Dose
MK 2206
Clinical Trials
Mutation
Growth
In Vitro Techniques

Keywords

  • Developmental therapeutics
  • MK-2206
  • Preclinical testing

ASJC Scopus subject areas

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

Cite this

Gorlick, R., Maris, J. M., Houghton, P. J., Lock, R., Carol, H., Kurmasheva, R. T., ... Smith, M. A. (2012). Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program. Pediatric Blood and Cancer, 59(3), 518-524. https://doi.org/10.1002/pbc.23412

Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program. / Gorlick, Richard; Maris, John M.; Houghton, Peter J.; Lock, Richard; Carol, Hernan; Kurmasheva, Raushan T.; Kolb, E. Anders; Keir, Stephen T.; Reynolds, C. Patrick; Kang, Min H.; Billups, Catherine A.; Smith, Malcolm A.

In: Pediatric Blood and Cancer, Vol. 59, No. 3, 09.2012, p. 518-524.

Research output: Contribution to journalArticle

Gorlick, R, Maris, JM, Houghton, PJ, Lock, R, Carol, H, Kurmasheva, RT, Kolb, EA, Keir, ST, Reynolds, CP, Kang, MH, Billups, CA & Smith, MA 2012, 'Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program', Pediatric Blood and Cancer, vol. 59, no. 3, pp. 518-524. https://doi.org/10.1002/pbc.23412
Gorlick R, Maris JM, Houghton PJ, Lock R, Carol H, Kurmasheva RT et al. Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program. Pediatric Blood and Cancer. 2012 Sep;59(3):518-524. https://doi.org/10.1002/pbc.23412
Gorlick, Richard ; Maris, John M. ; Houghton, Peter J. ; Lock, Richard ; Carol, Hernan ; Kurmasheva, Raushan T. ; Kolb, E. Anders ; Keir, Stephen T. ; Reynolds, C. Patrick ; Kang, Min H. ; Billups, Catherine A. ; Smith, Malcolm A. / Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program. In: Pediatric Blood and Cancer. 2012 ; Vol. 59, No. 3. pp. 518-524.
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abstract = "Background: MK-2206 is a small molecule allosteric inhibitor of Akt/PKB that is undergoing clinical trials for treatment of cancer. Procedures: MK-2206 was tested against the PPTP in vitro panel using a 96-hour exposure (1.0nM-10μM), and in vivo using thrice weekly dosing for a planned 4 weeks at its maximum tolerated dose (MTD) of 180mg/kg. Results: In vitro, the median relative IC 50 value for MK-2206 was 2.2μM. Four cell lines with IC 50 values<200nM included two ALL cell lines (COG-LL-317 and RS4;11), an AML cell line with an activating KIT mutation (Kasumi-1), and a Ewing sarcoma cell line (CHLA-10). In vivo, MK-2206 induced significant differences in EFS distribution compared to control in 12 of 29 (41{\%}) of the evaluable solid tumor xenografts and in 2 of 8 (25{\%}) of the evaluable ALL xenografts. Significant differences in EFS distribution were most frequently noted in the osteosarcoma panel (6 of 6). A single solid tumor xenograft (OS-31) had a greater than twofold increase in time to event compared to control animals, with all other solid tumor xenografts showing lesser degrees of tumor growth inhibition. Objective responses were not observed for either the solid tumor or ALL xenografts. Conclusions: MK-2206 showed its most consistent activity in vitro against ALL cell lines and in vivo against osteosarcoma xenografts. However, no objective responses were observed in solid tumor or ALL xenografts. Further preclinical work evaluating MK-2206 in pediatric models in the combination therapy setting may contribute to its pediatric development.",
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