TY  - JOUR
AU  - Capper, D
AU  - von Deimling, A
AU  - Brandes, AA
AU  - Carpentier, AF
AU  - Kesari, S
AU  - Sepulveda-Sanchez, JM
AU  - Wheeler, HR
AU  - Chinot, O
AU  - Cher, L
AU  - Steinbach, JP
AU  - Specenier, P
AU  - Rodon, J
AU  - Cleverly, A
AU  - Smith, C
AU  - Gueorguieva, I
AU  - Miles, C
AU  - Guba, SC
AU  - Desaiah, D
AU  - Estrem, ST
AU  - Lahn, MM
AU  - Wick, W
Y2  - 2020/12/21
Y1  - 2017/05/01
SN  - 1422-0067
UR  - http://hdl.handle.net/11343/257608
AB  - 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.
LA  - English
PB  - MDPI
T1  - Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine
DO  - 10.3390/ijms18050995
IS  - International Journal of Molecular Sciences
VL  - 18
IS  - 5
L1  - /bitstream/handle/11343/257608/PMC5454908.pdf?sequence=1&isAllowed=y
ER  -