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

  • Neurooncol Adv. 2020 Dec 3;3(1):vdaa165. doi: 10.1093/noajnl/vdaa165.
Eric A Horne  1  2 ,  Philippe Diaz  3  4 ,  Patrick J Cimino  5 ,  Erik Jung  6 ,  Cong Xu  1 ,  Ernest Hamel  7 ,  Michael Wagenbach  8 ,  Debra Kumasaka  9 ,  Nicholas B Wageling  4 ,  Daniel D Azorín  6 ,  Frank Winkler  6 ,  Linda G Wordeman  8 ,  Eric C Holland  9 ,  Nephi Stella  1  10
Affiliations
  • 1. Department of Pharmacology, University of Washington, Seattle, Washington, USA.
  • 2. Stella Therapeutics, Inc., Pacific Northwest Research Institute, Seattle, Washington, USA.
  • 3. Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana, USA.
  • 4. DermaXon LLC, Missoula, Montana, USA.
  • 5. Department of Pathology, University of Washington, Seattle, Washington, USA.
  • 6. Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
  • 7. Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
  • 8. Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA.
  • 9. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • 10. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
PMID: 33506204 DOI: 10.1093/noajnl/vdaa165
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 patient-derived (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.

Keywords
DNA-damage; interphase; microtubules; tumor microtubes.
Products