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

Neuro Oncol. 2015 Sep;17(9):1210-9. doi: 10.1093/neuonc/nov081. Epub 2015 May 12.


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.

Keywords: blood-brain barrier; brain tumors; efflux transport; molecularly targeted agents; p-glycoprotein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Antineoplastic Agents / pharmacokinetics*
  • 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
  • Phosphoinositide-3 Kinase Inhibitors*
  • Pyrimidines / pharmacokinetics*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Thiophenes / pharmacokinetics*


  • 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
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse