Preclinical modeling in glioblastoma patient-derived xenograft (GBM PDX) xenografts to guide clinical development of lisavanbulin - a novel tumor checkpoint controller targeting microtubules

Danielle M. Burgenske, Surabhi M Talele, Jenny L. Pokorny, Ann C. Mladek, Katrina K. Bakken, Brett L. Carlson, Mark A. Schroeder, Lihong He, Zeng Hu, Gautham Gampa, Matthew L. Kosel, Paul A. Decker, Gaspar J. Kitange, Anne Schmitt-Hoffmann, Felix Bachmann, Rachael A. Vaubel, Jeanette E. Eckel-Passow, Caterina Giannini, Paul McSheehy, Heidi A. LaneWilliam F. Elmquist, Jann N Sarkaria

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts. Methods: Mice bearing intracranial tumors received lisavanbulin +/-RT +/-TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis. Results: Lisavanbulin monotherapy showed significant benefit (P <. 01) in 9 of 14 PDXs tested (median survival extension 9%-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours postdose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, P = .0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, P = .06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, P = .0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, P = .04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (P = .01). Conclusions: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations, and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.

Original languageEnglish (US)
Pages (from-to)384-395
Number of pages12
JournalNeuro-Oncology
Volume24
Issue number3
DOIs
StatePublished - Mar 1 2022

Bibliographical note

Funding Information:
This study was supported by Basilea Pharmaceutica International Ltd.

Publisher Copyright:
© 2021 The Author(s).

Keywords

  • drug efficacy
  • glioblastoma
  • microtubule-targeting agents
  • patient-derived xenografts
  • Antineoplastic Agents, Alkylating/therapeutic use
  • Humans
  • Temozolomide/therapeutic use
  • Glioblastoma/pathology
  • Brain Neoplasms/pathology
  • Microtubules/metabolism
  • Animals
  • Heterografts
  • Mice

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article

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