Abstract
6-Acetyl-8-cyclopentyl-5-methyl-2-([5-(piperazin-1-yl)pyridin-2-yl]amino)pyrido(2,3-d)pyrimidin-7(8H)-one [palbociclib (PD-0332991)] is a cyclin-dependent kinase 4/6 inhibitor approved for the treatment of metastatic breast cancer and is currently undergoing clinical trials for many solid tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and has limited treatment options. The cyclin-dependent kinase 4/6 pathway is commonly dysregulated in GBM and is a promising target in treating this devastating disease. The blood-brain barrier (BBB) limits the delivery of drugs to invasive regions of GBM, where the efflux transporters P-glycoprotein and breast cancer resistance protein can prevent treatments from reaching the tumor. The purpose of this study was to examine the mechanisms limiting the effectiveness of palbociclib therapy in an orthotopic xenograft model. The in vitro intracellular accumulation results demonstrated that palbociclib is a substrate for both P-glycoprotein and breast cancer resistance protein. In vivo studies in transgenic mice confirmed that efflux transport is responsible for the limited brain distribution of palbociclib. There was an ∼115-fold increase in brain exposure at steady state in the transporter deficient mice when compared with wild-type mice, and the efflux inhibitor elacridar significantly increased palbociclib brain distribution. Efficacy studies demonstrated that palbociclib is an effective therapy when GBM22 tumor cells are implanted in the flank, but ineffective in an orthotopic (intracranial) model. Moreover, doses designed to mimic brain exposure were ineffective in treating flank tumors. These results demonstrate that efflux transport in the BBB is involved in limiting the brain distribution of palbociclib and this has critical implications in determining effective dosing regimens of palbociclib therapy in the treatment of brain tumors.
Footnotes
- Received July 30, 2015.
- Accepted September 8, 2015.
Funding for this work was supported by the National Institutes of Health [Grants RO1 CA138437, RO1 NS077921, and P50 CA108961]. K.E.P. was supported by the Ronald J. Sawchuk, Edward G. Rippie, Rowell, American Foundation for Pharmaceutical Education Pre-Doctoral, and University of Minnesota Doctoral Dissertation Fellowships.
Part of this work was previously presented: Parrish KE, Pokorny JL, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF (2013) BBB efflux pump activity limits brain penetration of palbociclib (PD0332991) in glioblastoma. Mol Cancer Ther 12 (11 Supplement):C81.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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