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

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.

• Authors: Sabine Mueller, Rintaro Hashizume, Xiaodong Yang, Ilan Kolkowitz, Aleksandra K Olow, Joanna Phillips, Ivan Smirnov, Maxwell W Tom, Michael D Prados, C David James, Mitchel S Berger, Nalin Gupta, Daphne A Haas-Kogan
• Journal: Neuro-oncology (Neuro Oncol) Vol. 16 Issue 3 Pg. 352-60 (Mar 2014) ISSN: 1523-5866 [Electronic] England
• PMID: 24305702 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Nuclear Proteins
• Pyrazoles
• Pyrimidines
• Pyrimidinones
• Protein-Tyrosine Kinases
• WEE1 protein, human
• adavosertib

Topics

• Animals
• Brain Neoplasms (genetics, therapy)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Death
• Cell Line, Tumor
• Chemoradiotherapy
• Glioblastoma (genetics, therapy)
• Humans
• Mice
• Mice, Transgenic
• Nuclear Proteins (antagonists & inhibitors, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Pyrazoles (therapeutic use)
• Pyrimidines (therapeutic use)
• Pyrimidinones