Targeting Wee1 for the treatment of pediatric high-grade gliomas

High-grade gliomas (HGGs) are aggressive brain tumors in children, with 5-year survival rates <20%. For diffuse intrinsic pontine gliomas (DIPGs), the most common type of glioma arising in the brainstem, the prognosis is even worse, with virtually no long-term survivors.1 Despite several decades of research efforts, the outcomes for these children have not significantly changed. This lack of progress can be attributed to a lack of understanding of underlying molecular events leading to pediatric HGG and DIPG tumorigenesis and a lack of relevant models for therapeutic drug testing. A number of genetic and molecular alterations have recently been identified in the oncogenesis of pediatric gliomas. Approximately 15% of pediatric gliomas (World Health Organization grades II–IV) have an activating mutation in the Braf gene (BRAFV600E). Inhibitors targeting components of this activated pathway are entering clinical trials for the treatment of children with BRAFV600E-positive gliomas.2 Platelet derived growth factor receptor (PDGFR) amplification has also been reported in subsets of HGGs and DIPGs, with crenolanib, an inhibitor of PDGFR kinase, currently being tested in children and young adults with the latter type of tumor.3 In addition, recent investigations have found a specific histone mutation (K27M-H3.3) that is present in most DIPGs, whose occurrence is associated with worse clinical outcome.4,5 Investigations targeting molecular biology related to this mutation are ongoing. The molecular underpinnings of pediatric HGGs and DIPGs are distinct from those underlying adult gliomas,6 and therefore the common practice of extrapolating adult therapies to pediatric tumors is precarious. The development of effective strategies for pediatric patients requires laboratory investigations and preclinical testing in relevant, pediatric-specific models. A potential specific molecular target is Wee1, which is a critical driver of G2-M cell cycle progression. Activated Wee1 causes inhibitory phosphorylation of Cdc2, preventing G2-M cell cycle progression. Inhibition of Wee1 in combination with radiation has been shown to reduce tumor growth in adult models of glioblastoma multiforme (GBM), by promoting premature mitosis in cells with damaged DNA.7 Wee1 inhibition alone has also been shown to have antitumor activity in sarcoma cells leading to apoptotic death.8 To date, possible links between Wee1 and known aberrations in pediatric HGG and/or DIPGs such as PDGFR amplification or the specific K27M-H3.3 mutation remain poorly understood. MK-1775 is a selective Wee1 kinase inhibitor and currently the only Wee1 inhibitor to enter early phase 1/2 clinical trials in combination with conventional chemotherapy for adults with advanced solid tumors. In this study, we investigated the expression of Wee1 in pediatric gliomas to evaluate its relevance as a therapeutic target and whether combining MK-1775 with radiation is more effective than radiation alone for the treatment of pediatric gliomas. To our knowledge this is the first investigation that reports on the expression of Wee1 in all grades of pediatric gliomas—including DIPG—and uses relevant pediatric glioma models to assess the effect of MK-1775 in combination with radiation.