دورية أكاديمية
أعرض في EDS

Preclinical modeling in glioblastoma patient-derived xenograft (GBM PDX) xenografts to guide clinical development of lisavanbulin-a novel tumor checkpoint controller targeting microtubules.

التفاصيل البيبلوغرافية
العنوان: Preclinical modeling in glioblastoma patient-derived xenograft (GBM PDX) xenografts to guide clinical development of lisavanbulin-a novel tumor checkpoint controller targeting microtubules.
المؤلفون: Burgenske DM; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Talele S; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA., Pokorny JL; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.; Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Mladek AC; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Bakken KK; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Carlson BL; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Schroeder MA; Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA., He L; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Hu Z; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Gampa G; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA., Kosel ML; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA., Decker PA; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA., Kitange GJ; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA., Schmitt-Hoffmann A, Bachmann F; Basilea Pharmaceutica International Ltd., Basel, Switzerland., Vaubel RA; Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., Eckel-Passow JE; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA., Giannini C; Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA., McSheehy P; Basilea Pharmaceutica International Ltd., Basel, Switzerland., Lane HA; Basilea Pharmaceutica International Ltd., Basel, Switzerland., Elmquist WF; Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA., Sarkaria JN; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA.
المصدر: Neuro-oncology [Neuro Oncol] 2022 Mar 12; Vol. 24 (3), pp. 384-395.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 100887420 Publication Model: Print Cited Medium: Internet ISSN: 1523-5866 (Electronic) Linking ISSN: 15228517 NLM ISO Abbreviation: Neuro Oncol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2010- : Oxford : Oxford University Press
Original Publication: 1999-<2002> : Charlottesville, VA : Carden Jennings Pub.,
مواضيع طبية MeSH: Brain Neoplasms*/pathology , Glioblastoma*/pathology, Animals ; Antineoplastic Agents, Alkylating/therapeutic use ; Heterografts ; Humans ; Mice ; Microtubules/metabolism ; Microtubules/pathology ; Temozolomide/therapeutic use
مستخلص: Background: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts.
Methods: Mice bearing intracranial tumors received lisavanbulin +/-RT +/-TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis.
Results: Lisavanbulin monotherapy showed significant benefit (P < .01) in 9 of 14 PDXs tested (median survival extension 9%-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours postdose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, P = .0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, P = .06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, P = .0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, P = .04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (P = .01).
Conclusions: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations, and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.
(© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
التعليقات: Comment in: Neuro Oncol. 2021 Nov 27;:. (PMID: 34850193)
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معلومات مُعتمدة: P30 CA015083 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: drug efficacy; glioblastoma; microtubule-targeting agents; patient-derived xenografts
المشرفين على المادة: 0 (Antineoplastic Agents, Alkylating)
YF1K15M17Y (Temozolomide)
تواريخ الأحداث: Date Created: 20210707 Date Completed: 20220322 Latest Revision: 20221213
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8917401
DOI: 10.1093/neuonc/noab162
PMID: 34232318
قاعدة البيانات: MEDLINE
الوصف
تدمد:1523-5866
DOI:10.1093/neuonc/noab162