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-amplified 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. Mol Cancer Ther; 17(9); 1893–901. ©2018 AACR.

中文翻译：

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MDM2 抑制剂 SAR405838 在胶质母细胞瘤中的疗效受限于跨血脑屏障的不良分布

围绕血脑屏障 (BBB) 的异质性破坏（如胶质母细胞瘤 (GBM) 中所见）是否导致足够的药物输送足以在 GBM 中发挥疗效，存在争议。当使用对完整 BBB 渗透性差的强效靶向药物时，这个问题尤其重要。鼠双分钟 2 (MDM2) 抑制剂 SAR405838 的功效在 GBM 的患者来源异种移植 (PDX) 模型中进行了测试。在具有不同 MDM2 表达的 PDX 模型中评估了 SAR405838 的体外功效，并评估了高 (GBM108) 和低 (GBM102) 表达的侧翼和原位功效。使用 TexasRed-3 kDa 葡聚糖评估的 BBB 通透性通过 VEGFA 过表达在 GBM108 中显着增加。给药、MRI、比较 BBB 完整（GBM108 载体）和 BBB 破坏（GBM108-VEGFA）模型之间的原位存活率。与体外和异位模型中的 MDM2 对照线相比，具有高 MDM2 表达的 MDM2 扩增的 PDX 线对 SAR405838 敏感。与在侧腹异种移植物中观察到的显着疗效相反，SAR405838 在原位肿瘤中无效。尽管在施用钆造影剂后 GBM108 载体和 GBM108-VEGFA 都可以在 MRI 上轻松成像，但根据 MA​​LDI-MSI 确定，GBM108-VEGFA 肿瘤的药物和钆积累显着增强。GBM108-VEGFA 中增强的药物递送转化为原位疗效的显着改善。这项研究清楚地表明，在部分完整的 BBB 中有限的药物分布可能会限制靶向药物在 GBM 中的疗效。在任何针对 GBM 的精准医学策略中，靶向药物的大脑渗透都是一个重要的考虑因素。摩尔癌症治疗; 17(9); 1893-901。©2018 AACR。