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

Abstract

<b>Purpose:</b> Bioinformatics analysis followed by <i>in vivo</i> 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 <i>MYC</i>-amplified tumors that have the worst clinical prognosis.<b>Experimental Design:</b> A protein interaction network derived from a <i>Sleeping Beauty</i> mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated <i>in vivo</i> using PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice.<b>Results:</b> 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 PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and <i>MYC</i>-amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing <i>MYC</i>-amplified intracranial tumors.<b>Conclusions:</b> Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and <i>MYC</i>-amplified group 3 medulloblastoma. <i>Clin Cancer Res; 23(19); 5802-13. ©2017 AACR</i>.