Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 17; no. 9; pp. 1210 - 1219
• Main Authors: Becker, C. M., Oberoi, R. K., McFarren, S. J., Muldoon, D. M., Pafundi, D. H., Pokorny, J. L., Brinkmann, D. H., Ohlfest, J. R., Sarkaria, J. N., Largaespada, D. A., Elmquist, W. F.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.09.2015
• Series: Editor's choice
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Basic and Translational Investigations; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain Neoplasms - metabolism; Brain Neoplasms - prevention & control; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Drug Delivery Systems; Glioblastoma - metabolism; Glioblastoma - prevention & control; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Pyrimidines - pharmacokinetics; Thiophenes - pharmacokinetics; TOR Serine-Threonine Kinases - antagonists & inhibitors; blood-brain barrier; efflux transport; molecularly targeted agents; p-glycoprotein; brain tumors
• ISSN: 1522-8517; 1523-5866; 1523-5866
• DOI: 10.1093/neuonc/nov081

Targeting drug delivery to invasive glioma cells is a particularly difficult challenge because these cells lie behind an intact blood-brain barrier (BBB) that can be observed using multimodality imaging. BBB-associated efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) influence drug distribution to these cells and may negatively impact efficacy. To test the hypothesis that efflux transporters influence brain pharmacokinetics/pharmacodynamics of molecularly targeted agents in glioma treatment, we assessed region-specific penetrance and molecular-targeting capacity for a PI3K/mTOR kinase inhibitor that has high substrate affinity for efflux transporters (GDC-0980) and an analog (GNE-317) that was purposely designed to have reduced efflux. Brain tumor penetrance of GDC-0980 and GNE-317 was compared between FVB/n wild-type mice and Mdr1a/b(-/-)Bcrp(-/-) triple-knockout mice lacking P-gp and BCRP. C57B6/J mice bearing intracranial GL261 tumors were treated with GDC-0980, GNE-317, or vehicle to assess the targeted pharmacokinetic/pharmacodynamic effects in a glioblastoma model. Animals treated with GNE-317 demonstrated 3-fold greater penetrance in tumor core, rim, and normal brain compared with animals dosed with GDC-0980. Increased brain penetrance correlated with decreased staining of activated p-Akt, p-S6, and p-4EBP1 effector proteins downstream of PI3K and mTOR. GDC-0980 is subject to active efflux by P-gp and BCRP at the BBB, while brain penetrance of GNE-317 is independent of efflux, which translates into enhanced inhibition of PI3K/mTOR signaling. These data show that BBB efflux by P-gp and BCRP is therefore an important determinant in both brain penetrance and molecular targeting efficacy in the treatment of invasive glioma cells.