ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy.

Abstract

PURPOSE:

Little is known about the optimal clinical use of ABT-888 (veliparib) for treatment of glioblastoma. ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma, because it may synergize with the standard-of-care temozolomide (TMZ). We have elucidated important factors controlling ABT-888 efficacy in glioblastoma.

EXPERIMENTAL DESIGN:

We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type (WT) and Abcb1/Abcg2-deficient (KO) recipients.

RESULTS:

ABT-888/TMZ is not efficacious against p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR allografts in wild-type recipients, indicating inherent resistance. Abcb1/Abcg2 mediated efflux of ABT-888 at the blood-brain barrier (BBB) causes a 5-fold reduction of ABT-888 brain penetration (P < 0.0001) that was fully reversible by elacridar. Efficacy studies in WT and KO recipients and/or concomitant elacridar demonstrate that Abcb1/Abcg2 at the BBB and in tumor cells impair TMZ/ABT-888 combination treatment efficacy. Elacridar also markedly improved TMZ/ABT-888 combination treatment in the spontaneous p53;p16(Ink4a)/p19(Arf);K-Ras(v12);LucR glioblastoma model. Importantly, ABT-888 does enhance TMZ efficacy in Pten deficient glioblastoma allografts and spontaneous tumors, even in Abcb1/Abcg2 proficient wild-type mice. Loss of PTEN occurs frequently in glioblastoma (36%) and in silico analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival (310 days vs. 620 days, n = 117).

CONCLUSIONS:

The potential of ABT-888 in glioblastoma can best be demonstrated in patients with PTEN null tumors. Therefore, clinical trials with ABT-888 should evaluate these patients as a separate group. Importantly, inhibition of ABCB1 and ABCG2 (by elacridar) may improve the efficacy of TMZ/ABT-888 therapy in all glioblastoma patients.

• Authors: Fan Lin, Mark C de Gooijer, Eloy Moreno Roig, Levi C M Buil, Susan M Christner, Jan H Beumer, Thomas Würdinger, Jos H Beijnen, Olaf van Tellingen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 10 Pg. 2703-13 (May 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24647572 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcg2 protein, mouse
• Acridines
• Benzimidazoles
• Tetrahydroisoquinolines
• veliparib
• Dacarbazine
• PTEN Phosphohydrolase
• Abcb1b protein, mouse
• Elacridar
• Temozolomide

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Acridines (administration & dosage, pharmacokinetics)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use)
• Area Under Curve
• Benzimidazoles (administration & dosage, pharmacokinetics)
• Blood-Brain Barrier (drug effects, metabolism)
• Blotting, Western
• Brain (drug effects, metabolism)
• Cell Line, Tumor
• Dacarbazine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Dogs
• Glioblastoma (drug therapy, genetics, pathology)
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• LLC-PK1 Cells
• Madin Darby Canine Kidney Cells
• Metabolic Clearance Rate
• Mice, Knockout
• Mice, Nude
• PTEN Phosphohydrolase (genetics, metabolism)
• Swine
• Temozolomide
• Tetrahydroisoquinolines (administration & dosage, pharmacokinetics)
• Treatment Outcome