Evidence map›Paper›PMID 25972455›Full record

ArticleNeuro-oncology2015

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 and 1 more

Open access · bronzeAbstract read

PubMed Full text at PMC Publisher

In one paragraph

Article in Neuro-oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it

0cells of the map it votes in

28citing papers in PubMed

2.4field-weighted citation impact, top 9% of its field

1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

28 citing papers in PubMed, 39 citations in OpenAlex.

GNE-317 ameliorates neuroinflammation stimulated by lipopolysaccharide via PI3K/Akt/mTOR pathway.Pharmacological reports : PR · 2026
Article
The impact of therapeutic radiation on drug distribution across the blood-brain barrier in normal mouse brain and orthotopic glioblastoma tumors.Neuro-oncology · 2025
Article
GNE-317 Reverses MSN-Mediated Proneural-to-Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
Article
Preclinical studies of histotripsy for intracranial tumors.Frontiers in neurology · 2025
Review
Engineered smart materials for RNA based molecular therapy to treat Glioblastoma.Bioactive materials · 2024
Article
Recent Advancements and Strategies for Overcoming the Blood-Brain Barrier Using Albumin-Based Drug Delivery Systems to Treat Brain Cancer, with a Focus on Glioblastoma.Polymers · 2023
Review
Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy.Theranostics · 2022
Review
The blood-tumour barrier in cancer biology and therapy.Nature reviews. Clinical oncology · 2021
Review
The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas.Cancer drug resistance (Alhambra, Calif.) · 2021
Review
Molecular Mechanisms of Treatment Resistance in Glioblastoma.International journal of molecular sciences · 2020
Review
Overexpression of ABCB1 and ABCG2 contributes to reduced efficacy of the PI3K/mTOR inhibitor samotolisib (LY3023414) in cancer cell lines.Biochemical pharmacology · 2020
Article
Zika virus-based immunotherapy enhances long-term survival of rodents with brain tumors through upregulation of memory T-cells.PloS one · 2020
Article
ABC Transporters at the Blood-Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas.Pharmaceutics · 2019
Review
RETRACTED: The Brain Penetrating and Dual TORC1/TORC2 Inhibitor, RES529, Elicits Anti-Glioma Activity and Enhances the Therapeutic Effects of Anti-Angiogenetic Compounds in Preclinical Murine Models.Cancers · 2019
Article
Targeting mTOR for cancer therapy.Journal of hematology & oncology · 2019
Review
The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity inClinical cancer research : an official journal of the American Association for Cancer Research · 2019
Article
Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier.Molecular cancer therapeutics · 2018
Article
Buparlisib is a brain penetrable pan-PI3K inhibitor.Scientific reports · 2018
Article
Barriers to Effective Drug Treatment for Brain Metastases: A Multifactorial Problem in the Delivery of Precision Medicine.Pharmaceutical research · 2018
Review
ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors.Investigational new drugs · 2018
Article

4 · The record

Corrections and comments

Commented on by
Blood-brain barrier-associated efflux transporters: a significant but underappreciated obstacle to drug development in glioblastoma.2015

5 · Who and what money

Authors and funding

11 authors at 4 institutions in 1 country.

Chani M BeckerDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

Rajneet K OberoiDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

Stephan J McFarrenDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

Daniel M MuldoonDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

Deanna H PafundiDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

Jenny L PokornyDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

Debra H BrinkmannDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

John R OhlfestDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

Jann N SarkariaDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

David A LargaespadaDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

William F ElmquistDepartment of Neuroscience, University of Minnesota, Minneapolis, Minnesota (C.M.B., S.J.M., D.M.M., J.R.O., W.F.E); Brain Tumor Program, University of Minnesota, Minneapolis, Minnesota (C.M.B., R.K.O., S.J.M., D.M.M., J.R.O., D.A.L., W.F.E); Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota (R.K.O., W.F.E); Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota (J.R.O., D.A.L); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (D.H.P., J.L.P., D.H.B., J.N.S); Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota

University of Minnesota · USTwin Cities Orthopedics · USMayo Clinic · USUniversity of Minnesota, Duluth · US

Funding

Women's Cancer ProgramP30CA015083 · NCI · MAYO CLINIC ROCHESTER · PI Felicity Enders · 1985 to 2026

$151.3M

Targeted MV-CEA as a Potent Antitumor Agent against GBMP50CA108961 · NCI · MAYO CLINIC ROCHESTER · PI O'NEILL, BRIAN PATRICK · 2004 to 2015

$22.5M

PREDOCTORAL TRAINING OF NEUROSCIENTISTST32GM008471 · NIGMS · UNIVERSITY OF MINNESOTA TWIN CITIES · PI EBNER, TIMOTHY J · 1993 to 2017

$4.9M

Influence of Anti-Angiogenic Therapy on Drug Delivery to Brain TumorsR01NS077921 · NINDS · UNIVERSITY OF MINNESOTA · PI ELMQUIST, WILLIAM, SARKARIA, JANN N. · 2012 to 2016

$2.5M

Improving Delivery of Molecularly-Targeted Therapy to Invasive Glioma CellsR01CA138437 · NCI · UNIVERSITY OF MINNESOTA · PI ELMQUIST, WILLIAM, OHLFEST, JOHN R · 2010 to 2014

$1.5M

NCI NIH HHS CA138437NCI NIH HHS P30 CA015083NCI NIH HHS P50 CA108961NIGMS NIH HHS T32 GM008471NINDS NIH HHS NS077921NINDS NIH HHS R01 NS077921

6 · The paper itself

Abstract

backgroundTargeting 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.

methodsBrain 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.

resultsAnimals 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.

conclusionsGDC-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.

Indexed as

Phosphoinositide-3 Kinase InhibitorsAnimalsAntineoplastic AgentsATP-Binding Cassette TransportersATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Blood-Brain BarrierBrainBrain NeoplasmsBridged Bicyclo Compounds, HeterocyclicDrug Delivery SystemsGlioblastomaMiceMice, Inbred C57BLMice, KnockoutPyrimidines1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-oneAbcg2 protein, mouseAntineoplastic AgentsATP-Binding Cassette TransportersATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2Bridged Bicyclo Compounds, HeterocyclicGNE-317mTOR protein, mousePhosphoinositide-3 Kinase InhibitorsPyrimidinesThiophenesTOR Serine-Threonine Kinasesblood-brain barrierbrain tumorsefflux transportmolecularly targeted agentsp-glycoprotein

Identifiers

PMID25972455

DOI10.1093/neuonc/nov081

PMCPMC4588756

OpenAlexW1893358364

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.