domingo, 15 de julio de 2018

Efficacy of the MDM2 inhibitor SAR405838 in glioblastoma is limited by poor distribution across the blood-brain barrier. - PubMed - NCBI

2018 Jul 3. pii: molcanther.0600.2017. doi: 10.1158/1535-7163.MCT-17-0600. [Epub ahead of print]

Efficacy of the MDM2 inhibitor SAR405838 in glioblastoma is limited by poor distribution across the blood-brain barrier.

Kim M1, Ma DJ2, Calligaris D3, Zhang S1, Feathers RW2, Vaubel RA2, Meaux I4, Mladek AC2, Parrish KE1, Jin F2, Barriere C4, Debussche L4, Watters J4, Tian S2, Decker PA2, Eckel-Passow JE2, Kitange GJ2, Johnson AJ2, Parney IF2, Anastasiadis PZ2, Agar NYR3, Elmquist WF1, Sarkaria JN5.

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Abstract

Controversy exists surrounding whether heterogeneous disruption of the blood-brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2-expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3kDa dextran, was significantly increased in GBM108 through VEGFA over-expression. Drug delivery, magnetic resonance imaging (MRI), and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison to MDM2 control lines in both in vitro and heterotopic models. In contrast to profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM.