Efflux Transporters at the Blood-Brain Barrier Limit Delivery and Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib (PD-0332991) in an Orthotopic Brain Tumor Model

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.

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

“…Like many other anti-tumor agents, palbociclib is also subject to efflux by BBB transporters. Recent in vivo studies showed that both P-gp and BCRP restricted brain penetration of palbociclib, resulting in low drug levels (28,29). Therefore, we compared brain concentrations in mice of palbociclib when used alone vs. in combination with everolimus.…”

Combination of palbociclib and radiotherapy for glioblastoma

“…Conflicting evidence is available. While Hashizume and colleagues reported sufficient levels of palbociclib in the brain, 11 the same group reported earlier results that demonstrated that palbociclib was a substrate for both P-glycoprotein and breast cancer resistance protein 10 and levels were 115-fold less than the transporter deficient mice when compared with wild-type mice. We did not measure the levels of palbociclib in the brain of orthotopic mice in our current study, however the amount of drug used (75 mg/kg/day) was sufficient to achieve an anti-proliferative effect and a significant extension in survival when combined with RT.…”

Restricted Delivery of Talazoparib Across the Blood–Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma

“…The concentration of many drugs is significantly lower at the infiltrating GBM rim as compared to the necrotic tumor core(28). This impaired drug delivery to infiltrating glioma may be associated with diminished efficacy of these drugs in orthotopic glioma models (32, 41–43). TAL mirrors these experiences by demonstrating a lack of orthotopic efficacy despite activity in heterotopic models.…”