Testing of the Akt/PKB inhibitor MK-2206 by the Pediatric Preclinical Testing Program.

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 (1.0 nM-10 µM), and in vivo using thrice weekly dosing for a planned 4 weeks at its maximum tolerated dose (MTD) of 180 mg/kg.

RESULTS:

In vitro, the median relative IC(50) value for MK-2206 was 2.2 µM. Four cell lines with IC(50) values < 200 nM 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.

• Authors: 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
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 59 Issue 3 Pg. 518-24 (Sep 2012) ISSN: 1545-5017 [Electronic] United States
• PMID: 22102563 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Female
• Heterocyclic Compounds, 3-Ring (therapeutic use)
• Humans
• Maximum Tolerated Dose
• Mice
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Xenograft Model Antitumor Assays