Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine
AuthorCapper, D; von Deimling, A; Brandes, AA; Carpentier, AF; Kesari, S; Sepulveda-Sanchez, JM; Wheeler, HR; Chinot, O; Cher, L; Steinbach, JP; ...
Source TitleInternational Journal of Molecular Sciences
University of Melbourne Author/sCher, Lawrence
AffiliationMedicine (Austin & Northern Health)
Document TypeJournal Article
CitationsCapper, D., von Deimling, A., Brandes, A. A., Carpentier, A. F., Kesari, S., Sepulveda-Sanchez, J. M., Wheeler, H. R., Chinot, O., Cher, L., Steinbach, J. P., Specenier, P., Rodon, J., Cleverly, A., Smith, C., Gueorguieva, I., Miles, C., Guba, S. C., Desaiah, D., Estrem, S. T. ,... Wick, W. (2017). Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 18 (5), https://doi.org/10.3390/ijms18050995.
Access StatusOpen Access
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2⁺ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H⁺ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3⁺ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4⁺ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.
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