Inhibition of CDK4/6 by Palbociclib significantly extends survival in Medulloblastoma patient-derived xenograft mouse models
Details
Publication Year 2017-09-01, Volume 7, Issue #9, Page pii: a025585
Journal Title
Clinical Cancer Research
Publication Type
Journal Article
Abstract
PURPOSE: <p>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.</p> <br />Experimental Design: <p>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.</p> <br />Results: <p>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. </p> <br />Conclusions:<br />Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC-amplified Group 3 medulloblastoma.
Publisher
AACR
WEHI Research Division(s)
Bioinformatics
PubMed ID
28637687
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-06-26 02:15:22
Last Modified: 2018-05-04 02:13:19
An error has occurred. This application may no longer respond until reloaded. Reload 🗙