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Testing of the Akt/PKB inhibitor MK-2206 by the Pediatric Preclinical Testing Program
Richard Gorlick1, John M Maris, Peter J Houghton
1The Children's Hospital at Montefiore, Bronx, New York, USA. rgorlick@montefiore.org
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.
Insights
MK-2206, an Akt inhibitor, showed activity against certain pediatric cancer cell lines in vitro and osteosarcoma xenografts in vivo. However, no objective responses were observed, suggesting further research in combination therapy is needed.
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- MK-2206 is an investigational small molecule allosteric inhibitor targeting Akt/PKB.
- This agent is currently being evaluated in clinical trials for various cancer treatments.
Purpose of the Study:
- To evaluate the efficacy of MK-2206 in preclinical cancer models.
- To assess its activity against acute lymphoblastic leukemia (ALL) and solid tumor xenografts.
- To determine its maximum tolerated dose (MTD) for in vivo studies.
Main Methods:
- In vitro testing against a panel of cancer cell lines using a 96-hour exposure.
- In vivo studies involving thrice-weekly dosing of MK-2206 at its MTD (180 mg/kg) in xenograft models.
- Evaluation of event-free survival (EFS) distribution and tumor growth inhibition.
Main Results:
- MK-2206 demonstrated activity in vitro, with notable efficacy against specific ALL, AML, and Ewing sarcoma cell lines (IC50 < 200 nM).
- In vivo, MK-2206 significantly impacted EFS in 41% of solid tumor xenografts and 25% of ALL xenografts, with consistent activity in osteosarcomas.
- While tumor growth inhibition was observed, no objective responses (e.g., complete or partial remission) were noted in either solid tumor or ALL xenografts.
Conclusions:
- MK-2206 exhibits the most consistent in vitro activity against ALL cell lines and in vivo activity against osteosarcoma xenografts.
- The lack of objective responses in preclinical models indicates a need for further investigation.
- Combination therapy approaches involving MK-2206 in pediatric cancer models warrant further preclinical evaluation for potential pediatric drug development.
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