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

被引:82
作者
Sangar, Michelle L. Cook [1 ]
Genovesi, Laura A. [2 ]
Nakamoto, Madison W. [1 ]
Davis, Melissa J. [3 ]
Knobluagh, Sue E. [4 ]
Ji, Pengxiang [2 ]
Millar, Amanda [2 ]
Wainwright, Brandon J. [2 ]
Olson, James M. [1 ]
机构
[1] Fred Hutchinson Canc Res Ctr, Clin Res Div, 1124 Columbia St, Seattle, WA 98104 USA
[2] Univ Queensland, Inst Mol Biosci, St Lucia, Qld, Australia
[3] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia
[4] Ohio State Univ, Coll Vet Med, Dept Vet Biosci, Columbus, OH 43210 USA
关键词
DEPENDENT KINASE 4/6; PD; 0332991; GLIOBLASTOMA XENOGRAFT; ANTITUMOR-ACTIVITY; PHASE-I; CYCLIN; CELLS; CDK6; IDENTIFICATION; PROGRESSION;
D O I
10.1158/1078-0432.CCR-16-2943
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Bioinformatics analysis followed by in vivo studies in patient-derived xenograft (PDX) models were used to identify and validate CDK4/6 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 G(1) 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. (C) 2017 AACR.
引用
收藏
页码:5802 / 5813
页数:12
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