Restricted delivery of talazoparib across the blood–brain barrier limits the sensitizing effects of PARP inhibition on temozolomide therapy in glioblastoma

Sani H. Kizilbash, Shiv K. Gupta, Kenneth Chang, Ryo Kawashima, Karen E. Parrish, Brett L. Carlson, Katrina K. Bakken, Ann C. Mladek, Mark A. Schroeder, Paul A. Decker, Gaspar J. Kitange, Yuqiao Shen, Ying Feng, Andrew A. Protter, William F. Elmquist, Jann N. Sarkaria

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1-3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2-M arrest in vitroIn vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days versus 50 days temozolomide (P = 0.005), 11 days placebo (P < 0.001)]. However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts [median survival 37 vs. 30 days with temozolomide (P = 0.93), 14 days with placebo, P < 0.001]. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp-/- versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b-/- mice was higher than WT mice (0.23 vs. 0.02, P < 0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts.

Original languageEnglish (US)
Pages (from-to)2735-2746
Number of pages12
JournalMolecular Cancer Therapeutics
Volume16
Issue number12
DOIs
StatePublished - Dec 2017

Bibliographical note

Funding Information:
The study was supported by the NIH grants R03 CA201612 (to S.K. Gupta), R01 CA176830 (to J.N. Sarkaria), RO1 CA138437 (to W.F. Elmquist), R01 NS77921 (to W.F. Elmquist and J.N. Sarkaria), and P50 CA108961. S.K. Gupta is partly supported through Eagles Cancer Funds, Mayo Clinic Cancer Center.

Funding Information:
We thank Ms. Xiaoyue Chen, PhD student at Mayo Graduate School for advice on Ki-76 immunofluorescence, Mayo Optical Morphology and Flow Cytometry Core for help with flow cytometry; Analytical Biochemistry Core, University of Minnesota Masonic Cancer Center for help with LC-MS, and BioMarin Pharmaceuticals Inc. for supply of talazoparib. The study was supported by the NIH grants R03 CA201612 (to S.K. Gupta), R01 CA176830 (to J.N. Sarkaria), RO1 CA138437 (to W.F. Elmquist), R01 NS77921 (to W.F. Elmquist and J.N. Sarkaria), and P50 CA108961. S.K. Gupta is partly supported through Eagles Cancer Funds, Mayo Clinic Cancer Center.

Publisher Copyright:
© 2017 American Association for Cancer Research.

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