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. 2016 Oct;63(10):1744-52.
doi: 10.1002/pbc.26064. Epub 2016 May 30.

Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program

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Free PMC article

Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program

Min H Kang et al. Pediatr Blood Cancer. .
Free PMC article

Abstract

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 μM 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 μM for TP53 wild-type cell lines versus >10 μM 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.

Keywords: developmental therapeutics; pi3k inhibitor; preclinical testing.

Conflict of interest statement

Conflict of interest statement: The authors consider that there are no actual or perceived conflicts of interest.

Figures

Figure 1
Figure 1
MK-8242 in vitro activity: A. The median rIC50 ratio graph shows the relative rIC50 values for the cell lines of the PPTP panel. Each bar represents the ratio of the panel rIC50 to the rIC50 value of the indicated cell line. Bars to the right represent cell lines with higher sensitivity, while bars to the left indicate cell lines with lesser sensitivity. B. Relationship between TP53 status and sensitivity (hatched bars WT p53, solid bars, Mutant p53).
Figure 2
Figure 2
MK-8242 in vivo objective response activity for non-glioblastoma brain tumor models. Medulloblastomas (BT-28 and BT-50) and two ependymoma lines (BT-36, BT-41). A. Kaplan-Meier curves for EFS, B. median relative tumor volume graphs, and C. individual tumor volume graphs are shown for selected lines. Control (gray lines); Treated (black lines), statistical significance (p values) of the difference between treated and control groups are included.
Figure 3
Figure 3
MK-8242 in vivo objective response activity for ALL models. ALL-2 (B-precursor), ALL-4 (B-precursor; BCR-ABL), ALL-8 (T-cell ALL) and MLL-7 (Infant, Precursor B-ALL). A. Kaplan-Meier curves showing the EFS, B. median leukemia engraftment as detected in peripheral blood, and C. individual leukemia engraftment (right). Controls (gray lines); Treated (black lines), statistical significance (p values) of the difference between treated and control groups are included.
Figure 4
Figure 4
A. The colored heat map depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥2 but <6, and low activity by a score of <2. Lines with bolded font have mutant TP53 or very low TP53 expression (osteosarcomas). B. Representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.

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