Dissemin is shutting down on January 1st, 2025

Published in

American Association for Cancer Research, Clinical Cancer Research, 19(23), p. 5802-5813, 2017

DOI: 10.1158/1078-0432.ccr-16-2943

Links

Tools

Export citation

Search in Google Scholar

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

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

Full text: Download

Green circle
Preprint: archiving allowed
Orange circle
Postprint: archiving restricted
Red circle
Published version: archiving forbidden
Data provided by SHERPA/RoMEO

Abstract

Abstract Purpose: Bioinformatics analysis followed by in vivo 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 MYC-amplified tumors that have the worst clinical prognosis. Experimental Design: 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 PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice. Results: 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 MYC-amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing MYC-amplified intracranial tumors. Conclusions: Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC-amplified group 3 medulloblastoma. Clin Cancer Res; 23(19); 5802–13. ©2017 AACR.