PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models
Menée à l'aide de modèles murins, cette étude met en évidence l'intérêt de deux inhibiteurs de la voie de signalisation PI3K-mTOR dans le traitement des gliomes de haut grade
Purpose : The PI3K–AKT–mTOR signaling pathway is frequently activated in glioblastoma and offers several druggable targets. However, clinical efficacy of PI3K/mTOR inhibitors in glioblastoma has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against glioblastoma. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood–brain barrier (BBB) restricts the brain penetration of many drugs. Experimental Design : We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wild-type and ABC-transporter knockout mice. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models. Results : The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1, whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055, but not ZSTK474 or rapamycin. Concordantly, Abcb1a/b−/−;Abcg2−/− mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold), and NVP-BEZ235 (4.5-fold), but not ZSTK474 relative to WT mice. Importantly, ABC transporters limited rapamycin brain penetration to subtherapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition. NVP-BEZ235 and ZSTK474 demonstrated antitumor efficacy with improved survival against U87 orthotopic gliomas, although the effect of ZSTK474 was more pronounced. Finally, ZSTK474 prolonged overall survival in Cre-LoxP conditional transgenic Pten;p16Ink4a/p19Arf;K-Rasv12;LucR mice, mainly by delaying tumor onset. Conclusions : PI3K/mTOR inhibitors with weak affinities for ABC transporters can achieve target inhibition in brain (tumors), but have modest single-agent efficacy and combinations with (BBB penetrable) inhibitors of other activated pathways may be required. Clin Cancer Res; 1–13. ©2016 AACR.