Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models

Abstract

Bioinformatics analysis followed by in vivo studies in patient-derived xenograft models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly Group 3 MYC-amplified tumors which have the worst clinical prognosis. A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated in vivo using patient-derived xenograft models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice. Informatics analysis identified the CDK4/6/CYCLIN D/RB pathway as a novel “druggable” pathway for multiple subgroups of medulloblastoma. Palbociclib, a highly specific inhibitor of CDK4/6, was found to inhibit RB phosphorylation and cause G1 arrest in patient-derived xenograft (PDX) models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and MYC-amplified Group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing MYC-amplified intracranial tumors. Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC -amplified Group 3 medulloblastoma.