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

Bioinformatics analysis followed by studies in patient-derived xenograft (PDX) models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly group 3 -amplified tumors that have the worst clinical prognosis. A protein interaction network derived from a mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated using PDX 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 G arrest in PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and -amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing -amplified intracranial tumors. Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and -amplified group 3 medulloblastoma. .