A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Eric A. Horne, Philippe Diaz, Patrick J. Cimino, Erik Jung, Cong Xu, Ernest Hamel, Michael Wagenbach, Debra Kumasaka, Nicholas B. Wageling, Daniel D. Azorín, Frank Winkler, Linda G. Wordeman, Eric C. Holland, Nephi Stella

Research output: Contribution to journalArticlepeer-review

Abstract

Background. Glioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA. Methods. Synthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patientderived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model. Results. We discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT). Conclusion. Our study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs.

Original languageEnglish
Article numbervdaa165
JournalNeuro-Oncology Advances
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • DNA-damage
  • interphase
  • microtubules
  • tumor microtubes

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