2. Academic Validation
  3. A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

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

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.

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