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Neuro Oncol. 2014 Mar;16(3):352-60. doi: 10.1093/neuonc/not220. Epub 2013 Dec 4.

Targeting Wee1 for the treatment of pediatric high-grade gliomas.

Author information

1
Department of Neurology, University of California, San Francisco, San Francisco, California (S.M., I.K.); Department of Pediatrics, University of California, San Francisco, San Francisco, California (S.M., M.D.P., N.G.); Brain Tumor Research Center, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California (S.M., R.H., X.Y., A.K.O., J.P., M.W.T., C.D.J., M.S.B., N.G., D.A.H.-K.); Department of Neurological Surgery, University of California, San Francisco, San Francisco, California (S.M., J.P., I.S., M.D.P., C.D.J., M.S.B., N.G., D.A.H.-K.); Department of Radiation Oncology, University of California, San Francisco, San Francisco, California (D.A.H.-K.).

Abstract

BACKGROUND:

We investigated the efficacy of the Wee1 inhibitor MK-1775 in combination with radiation for the treatment of pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas (DIPGs).

METHODS:

Gene expression analysis was performed for 38 primary pediatric gliomas (3 grade I, 10 grade II, 11 grade III, 14 grade IV) and 8 normal brain samples using the Agilent 4 × 44 K array. Clonogenic survival assays were carried out in pediatric and adult HGG cell lines (n = 6) to assess radiosensitizing effects of MK-1775. DNA repair capacity was evaluated by measuring protein levels of γ-H2AX, a marker of double strand DNA breaks. In vivo activity of MK-1775 with radiation was assessed in 2 distinct orthotopic engraftment models of pediatric HGG, including 1 derived from a genetically engineered mouse carrying a BRAF(V600E) mutation, and 1 xenograft model in which tumor cells were derived from a patient's DIPG.

RESULTS:

Wee1 is overexpressed in pediatric HGGs, with increasing expression positively correlated with malignancy (P = .007 for grade III + IV vs I + II) and markedly high expression in DIPG. Combination treatment of MK-1775 and radiation reduced clonogenic survival and increased expression of γ-H2AX to a greater extent than achieved by radiation alone. Finally, combined MK-1775 and radiation conferred greater survival benefit to mice bearing engrafted, orthotopic HGG and DIPG tumors, compared with treatment with radiation alone (BRAF(V600E) model P = .0061 and DIPG brainstem model P = .0163).

CONCLUSION:

Our results highlight MK-1775 as a promising new therapeutic agent for use in combination with radiation for the treatment of pediatric HGGs, including DIPG.

KEYWORDS:

MK-1775; Wee1 inhibition; diffuse intrinsic pontine glioma; pediatric high-grade glioma; radiation

PMID:
24305702
PMCID:
PMC3922515
DOI:
10.1093/neuonc/not220
[Indexed for MEDLINE]
Free PMC Article
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