Data from ABCB1, ABCG2, and PTEN Determine the Response of Glioblastoma to Temozolomide and ABT-888 Therapy

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> We used genetically engineered spontaneous glioblastoma mouse models and allograft models that were orthotopically transplanted into wild-type (WT) and <i>Abcb1/Abcg2</i>-deficient (KO) recipients.</p><p><b>Results:</b> ABT-888/TMZ is not efficacious against <i>p53;p16<sup>Ink4a</sup>/p19<sup>Arf</sup>;K-Ras<sup>v12</sup>;LucR</i> 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 (<i>P</i> < 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 <i>p53;p16<sup>Ink4a</sup>/p19<sup>Arf</sup>;K-Ras<sup>v12</sup>;LucR</i> glioblastoma model. Importantly, ABT-888 does enhance TMZ efficacy in <i>Pten</i> deficient glioblastoma allografts and spontaneous tumors, even in <i>Abcb1/Abcg2</i> proficient wild-type mice. Loss of <i>PTEN</i> occurs frequently in glioblastoma (36%) and <i>in silico</i> analysis on patient with glioblastoma samples revealed that it is associated with a worse overall survival (310 days vs. 620 days, <i>n</i> = 117).</p><p><b>Conclusions:</b> The potential of ABT-888 in glioblastoma can best be demonstrated in patients with <i>PTEN</i> 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. <i>Clin Cancer Res; 20(10); 2703–13. ©2014 AACR</i>.</p></div>