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

doi:10.1093/noajnl/vdaa165

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 journal › Article › peer-review

24 Scopus citations

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 language	English
Article number	vdaa165
Journal	Neuro-Oncology Advances
Volume	3
Issue number	1
DOIs	https://doi.org/10.1093/noajnl/vdaa165
State	Published - Jan 1 2021

Funding

Disclaimer. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This work was supported by the National Institutes of Health [P20GM103546, P30NS055022 to P.D. and R.R.P.] [R41NS105304, R43AR076842 to P.D. and N.B.W.] [R43CA165452 to E.C.H.] [R21NS106924, R01CA244213 to N.S. and L.W.] [R01GM069429 to M.W. and L.W.] and the German Research Foundation [SFB 1389 to F.W., E.J., and D.D.A.].

Funder number
R43CA165452, R21NS106924, R41NS105304, P20GM103546, P30NS055022, R01CA244213, R43AR076842, R01GM069429
HHSN261200800001E
SFB 1389

Keywords

DNA-damage
interphase
microtubules
tumor microtubes

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10.1093/noajnl/vdaa165

Cite this

Horne, E. A., Diaz, P., Cimino, P. J., Jung, E., Xu, C., Hamel, E., Wagenbach, M., Kumasaka, D., Wageling, N. B., Azorín, D. D., Winkler, F., Wordeman, L. G., Holland, E. C., & Stella, N. (2021). A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis. Neuro-Oncology Advances, 3(1), Article vdaa165. https://doi.org/10.1093/noajnl/vdaa165

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title = "A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis",

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.",

keywords = "DNA-damage, interphase, microtubules, tumor microtubes",

author = "Horne, \{Eric A.\} and Philippe Diaz and Cimino, \{Patrick J.\} and Erik Jung and Cong Xu and Ernest Hamel and Michael Wagenbach and Debra Kumasaka and Wageling, \{Nicholas B.\} and Azor{\'i}n, \{Daniel D.\} and Frank Winkler and Wordeman, \{Linda G.\} and Holland, \{Eric C.\} and Nephi Stella",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2020.",

year = "2021",

month = jan,

day = "1",

doi = "10.1093/noajnl/vdaa165",

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T1 - A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

AU - Horne, Eric A.

AU - Diaz, Philippe

AU - Cimino, Patrick J.

AU - Jung, Erik

AU - Xu, Cong

AU - Hamel, Ernest

AU - Wagenbach, Michael

AU - Kumasaka, Debra

AU - Wageling, Nicholas B.

AU - Azorín, Daniel D.

AU - Winkler, Frank

AU - Wordeman, Linda G.

AU - Holland, Eric C.

AU - Stella, Nephi

PY - 2021/1/1

Y1 - 2021/1/1

N2 - 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.

AB - 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.

KW - DNA-damage

KW - interphase

KW - microtubules

KW - tumor microtubes

UR - https://www.scopus.com/pages/publications/85118833275

U2 - 10.1093/noajnl/vdaa165

DO - 10.1093/noajnl/vdaa165

M3 - Article

AN - SCOPUS:85118833275

SN - 2632-2498

VL - 3

JO - Neuro-Oncology Advances

JF - Neuro-Oncology Advances

IS - 1

M1 - vdaa165

ER -

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

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Keywords

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