Efficacy of PI3K-mTOR inhibition in high-grade glioma

Purpose: The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma (GBM) and offers several drugable targets. However, clinical efficacy of PI3K/mTOR inhibitors in GBM has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against GBM. 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 wildtype 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 sub-therapeutic 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. Lastly, 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.

from Cancer via ola Kala on Inoreader http://ift.tt/2byOg1Y
via IFTTT