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-3 kDa dextran, was significantly increased in GBM108 through VEGFA overexpression. Drug delivery, MRI, and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-ampli-fied PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison with MDM2 control lines in both in vitro and heterotopic models. In contrast with 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.
Bibliographical noteFunding Information:
The authors would like to thank Sanofi-Aventis for provision of SAR405838. We would like to thank Katie Bakken, Brett Carlson, and Mark Schroeder for the animal work in this article. This study was supported by Sanofi-Aventis and Mayo Clinic. Additional funding by the National Institutes of Health Public Health Service grants: CA90628 (to D.J. Ma), CA138437 (to W.F. Elmquist), NS077921 (to W.F. Elmquist and J.N. Sarkaria), CA186976 (to A.J. Johnson), the Mayo SPORE in Brain Cancer CA108961 (to J.N. Sarkaria), and MIT/Mayo Physical Sciences Center for Drug Distribution and Efficacy in Brain Tumors, U54CA210180 (to J.N. Sarkaria and W.F. Elmquist).