Abstract
Typical survival for pediatric high-grade gliomas remains less than 18 months despite recent improved understanding of the molecular drivers of these tumors. Hyperactivating MAPK and CDK4/6 pathway mutations are common and targetable alterations implicated in tumorigenesis and malignant transformation in pediatric glioma. We have established and characterized a novel patient-derived xenograft (PDX) model, RHT128, from a pediatric patient diagnosed with the high-grade glioma anaplastic pleomorphic xanthoastrocytoma (APXA). The molecular landscape of PDX RHT128 exhibits molecular fidelity to the patient’s tumor. Clinical precision genomics analysis of the tumor revealed a novel BRAF chromosomal rearrangement and CDKN2A/B deletion. Based on this molecular signature, the patient was treated with MEK inhibitor trametinib as a monotherapy and, following progression of disease, with CDK4/6 inhibitor ribociclib. However, the tumor continued to progress. In this study our objective is to simultaneously target the CDK4/6 and MAPK pathways in RHT128 and determine to what extent this combination therapy minimizes emergence of therapeutic resistance. Single-agent efficacy assessments in a subcutaneous RHT128 model, showing significant dose-dependent reduction in tumor volume after treatment with abemaciclib (p<0.05), palbociclib (p<0.01), and the blood-brain barrier-permeable MEK inhibitor mirdametinib (p<0.0001). Analysis of the global kinome in CDK4/6 inhibitor-treated PDX tissues compared to vehicle treatment using multiplexed-inhibitor bead chromatography–mass spectrometry demonstrated effective inhibition of CDK4/6. Moreover, this analysis revealed dose-dependent alterations in the MAPK and PI3K pathways and modulation of critical neurotransmitter pathways in treated tissues. Future studies will explore efficacy of these MEK and CDK4/6 inhibitors in combination and in our BRAF wild-type and BRAF V600E variant APXA models to gain further mechanistic insights. The pervasiveness of alterations to the MAPK and CDK4/6 pathways in pediatric gliomas make this approach promising for further study in a broader range of these deadly tumors.