Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Neuro-oncology advances, 2021-01, Vol.3 (1), p.vdaa165

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. 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. 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). 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.