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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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<sup>-/-</sup>Bcrp<sup>-/-</sup> 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.

Original languageEnglish (US)
Pages (from-to)1210-1219
Number of pages10
JournalNeuro-Oncology
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Fingerprint

Penetrance
Glioblastoma
Phosphatidylinositol 3-Kinases
P-Glycoprotein
Blood-Brain Barrier
Brain
Glioma
Breast Neoplasms
Proteins
Pharmacokinetics
S 6
Drug Delivery Systems
Knockout Mice
Brain Neoplasms
Neoplasms
Phosphotransferases
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
GNE-317
Staining and Labeling
Pharmaceutical Preparations

Keywords

  • blood-brain barrier
  • brain tumors
  • efflux transport
  • molecularly targeted agents
  • p-glycoprotein

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Becker, C. M., Oberoi, R. K., McFarren, S. J., Muldoon, D. M., Pafundi, D. H., Pokorny, J. L., ... Elmquist, W. F. (2015). Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma. Neuro-Oncology, 17(9), 1210-1219. https://doi.org/10.1093/neuonc/nov081

Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma. / Becker, Chani M.; Oberoi, Rajneet K.; McFarren, Stephan J.; Muldoon, Daniel M.; Pafundi, Deanna H.; Pokorny, Jenny L.; Brinkmann, Debra H; Ohlfest, John R.; Sarkaria, Jann N; Largaespada, David A.; Elmquist, William F.

In: Neuro-Oncology, Vol. 17, No. 9, 01.09.2015, p. 1210-1219.

Research output: Contribution to journalArticle

Becker, CM, Oberoi, RK, McFarren, SJ, Muldoon, DM, Pafundi, DH, Pokorny, JL, Brinkmann, DH, Ohlfest, JR, Sarkaria, JN, Largaespada, DA & Elmquist, WF 2015, 'Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma', Neuro-Oncology, vol. 17, no. 9, pp. 1210-1219. https://doi.org/10.1093/neuonc/nov081
Becker, Chani M. ; Oberoi, Rajneet K. ; McFarren, Stephan J. ; Muldoon, Daniel M. ; Pafundi, Deanna H. ; Pokorny, Jenny L. ; Brinkmann, Debra H ; Ohlfest, John R. ; Sarkaria, Jann N ; Largaespada, David A. ; Elmquist, William F. / Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma. In: Neuro-Oncology. 2015 ; Vol. 17, No. 9. pp. 1210-1219.
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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.",
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T1 - Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma

AU - Becker, Chani M.

AU - Oberoi, Rajneet K.

AU - McFarren, Stephan J.

AU - Muldoon, Daniel M.

AU - Pafundi, Deanna H.

AU - Pokorny, Jenny L.

AU - Brinkmann, Debra H

AU - Ohlfest, John R.

AU - Sarkaria, Jann N

AU - Largaespada, David A.

AU - Elmquist, William F.

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N2 - 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.

AB - 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.

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