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Clin Cancer Res. 2015 Apr 15;21(8):1916-24. doi: 10.1158/1078-0432.CCR-14-2588. Epub 2015 Jan 21.

The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma.

Author information

1
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
2
Department of Neurosurgery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
3
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
4
Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
5
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Boston, Massachusetts.
6
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., West Point, Pennsylvania.
7
Department of Oncology, Merck & Co., Boston, Massachusetts.
8
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
9
Department of Neurosurgery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Radiology, Brigham and Women's Hospital and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
10
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. sarkaria.jann@mayo.edu.

Abstract

PURPOSE:

Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in glioblastoma multiforme (GBM) xenograft models alone and in combination with radiation and/or temozolomide.

EXPERIMENTAL DESIGN:

In vitro MK-1775 efficacy alone and in combination with temozolomide, and the impact on DNA damage, was analyzed by Western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI)-MS imaging.

RESULTS:

GBM22 (IC50 = 68 nmol/L) was significantly more sensitive to MK-1775 compared with five other GBM xenograft lines, including GBM6 (IC50 >300 nmol/L), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with temozolomide in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with temozolomide, whereas in a flank model of GBM22, MK-1775 exhibited both single-agent and combinatorial activity with temozolomide. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared with heterotopic GBM22 tumors.

CONCLUSIONS:

Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM.

PMID:
25609063
PMCID:
PMC4401631
DOI:
10.1158/1078-0432.CCR-14-2588
[Indexed for MEDLINE]
Free PMC Article

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