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

Abstract

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..

Hedgehog signaling drives medulloblastoma growth via CDK6

“…Furtherof uncontrolled cell proliferation in medulloblastoma regardless of genetic etiology (Supplemental Figure 1E). In support of this hypothesis, small molecule inhibition of CDK6 confers a survival benefit in mice bearing patient-derived xenographs of group 3 medulloblastomas (14).…”

Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in Myc-driven Medulloblastoma

“…The efficacy of THZ2 in medulloblastoma cell line orthotopic xenografts instigated more direct studies using the patient-derived xenograft, MED411FH (PDX411) (Cook Sangar et al, 2017).…”

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

“…An alternative pharmacologic target of oncogenic HH signaling in medulloblastoma is cyclin-dependent kinase 6 (CDK6), a mitogenic kinase and direct transcriptional target of GLI2 ( Figure 3 and refs. 90,91). When activated through interaction with cyclin D1, CDK6 induces cell cycle progression by phosphorylating the tumor suppressor RB and relieving repression of E2F transcription factors.…”