A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis. Issue 1 (3rd December 2020)

• Record Type: Journal Article
• Authors: Horne, Eric A; Diaz, Philippe; Cimino, Patrick J; Jung, Erik; Xu, Cong; Hamel, Ernest; Wagenbach, Michael; Kumasaka, Debra; Wageling, Nicholas B; Azorín, Daniel D; Winkler, Frank; Wordeman, Linda G; Holland, Eric C; Stella, Nephi
• Is Part Of: Neuro-oncology advances. Volume 3:Issue 1(2021)
• Publication Date: 2020-12-03
• Subjects: DNA-damage -- interphase -- microtubules -- tumor microtubes; 616.99481
• DOI: 10.1093/noajnl/vdaa165
• Languages: English
• ISSNs: 2632-2498

Abstract

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.