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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Chani M Becker, Rajneet K Oberoi, Stephan J McFarren, Daniel M Muldoon, Deanna H Pafundi, Jenny L Pokorny, Debra H Brinkmann, John R Ohlfest, Jann N Sarkaria, David A Largaespada, William F Elmquist
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 9 Pg. 1210-9 (Sep 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25972455 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcg2 protein, mouse
• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• GNE-317
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Thiophenes
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics)
• Animals
• Antineoplastic Agents (pharmacokinetics)
• Blood-Brain Barrier (metabolism)
• Brain (drug effects)
• Brain Neoplasms (metabolism, prevention & control)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacokinetics)
• Drug Delivery Systems
• Glioblastoma (metabolism, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines (pharmacokinetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Thiophenes (pharmacokinetics)