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Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program
Min H Kang1, C Patrick Reynolds1, E Anders Kolb2
1Cancer Center, Texas Tech University Health Sciences Center, Lubbock, Texas.
Background:
MK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction.
Procedures:
MK-8242 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10.0 microM and against the PPTP in vivo xenograft panels using oral gavage on Days 1-5 and Day 15-19 at a dose of 125 mg/kg (solid tumors) or 75 mg/kg (acute lymphoblastic leukemia [ALL] models).
Results:
The median IC50 for MK-8242 was 0.07 microM for TP53 wild-type cell lines versus >10 microM for TP53 mutant cell lines. MK-8242 induced a twofold or greater delay in time to event in 10 of 17 (59%) of TP53 wild-type solid tumor xenografts, excluding osteosarcoma xenografts that have very low TP53 expression. Objective responses were observed in seven solid tumor xenografts representing multiple histotypes. For the systemic-disease ALL panel, among eight xenografts there were two complete responses (CRs) and six partial responses (PRs). Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously showed maintained CR and PR, respectively. The expected pharmacodynamic responses to TP53 activation were observed in TP53 wild-type models treated with MK-8242. Pharmacokinetic analysis showed that MK-8242 drug exposure in SCID mice appears to exceed that was observed in adult phase 1 trials.
Conclusions:
MK-8242-induced tumor regressions across multiple solid tumor histotypes and induced CRs or PRs for most ALL xenografts. This activity was observed at MK-8242 drug exposures that appear to exceed those observed in human phase 1 trials.
Insights
MK-8242, an MDM2 inhibitor, shows significant anti-tumor activity by stabilizing TP53. This drug demonstrated efficacy in preclinical models of solid tumors and acute lymphoblastic leukemia (ALL), with exposures exceeding those in human trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- MK-8242 is an MDM2 inhibitor designed to stabilize the tumor suppressor protein TP53.
- TP53 stabilization by MK-8242 is intended to induce downstream effects like growth arrest or apoptosis in cancer cells.
Purpose of the Study:
- To evaluate the preclinical efficacy of MK-8242 in a diverse panel of pediatric cancer models.
- To assess the in vitro and in vivo activity of MK-8242 against solid tumors and acute lymphoblastic leukemia (ALL).
Main Methods:
- In vitro testing of MK-8242 against cell lines across a concentration range (1.0 nM to 10.0 microM).
- In vivo xenograft studies using oral gavage in mice at specific doses for solid tumors (125 mg/kg) and ALL (75 mg/kg).
Main Results:
- MK-8242 exhibited potent activity against TP53 wild-type cell lines (median IC50 0.07 microM).
- Significant tumor growth delay was observed in 59% of TP53 wild-type solid tumor xenografts.
- Complete or partial responses were noted in multiple solid tumor histotypes and most ALL xenografts.
Conclusions:
- MK-8242 demonstrated tumor regressions in various solid tumors and significant responses in ALL models.
- Observed drug exposures in mice exceeded those from human Phase 1 trials, suggesting potential for clinical efficacy.
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