TY  - JOUR
A1  - Capper, David
A1  - Deimling, Andreas von
A1  - Brandes, Alba
A1  - Carpentier, Antoine F.
A1  - Kesari, Santosh
A1  - Sepulveda-Sanchez, Juan M.
A1  - Wheeler, Helen Rippier
A1  - Chinot, Olivier
A1  - Cher, Lawrence
A1  - Steinbach, Joachim Peter
A1  - Specenier, Pol
A1  - Rodon, Jordi
A1  - Cleverly, Ann
A1  - Smith, Claire
A1  - Gueorguieva, Ivelina
A1  - Miles, Colin
A1  - Guba, Susan
A1  - Desaiah, Durisala
A1  - Estrem, Shawn T.
A1  - Lahn, Michael
A1  - Wick, Wolfgang
T1  - Biomarker and histopathology evaluation of patients with recurrent glioblastoma treated with galunisertib, lomustine, or the combination of galunisertib and lomustine
T2  - International journal of molecular sciences
N2  - 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.
KW  - galunisertib monohydrate (LY2157299)
KW  - TGF-β
KW  - pSMAD2
KW  - CDK4/CDK6
KW  - biomarkers
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45684
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-456846
SN  - 1422-0067
SN  - 1661-6596
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
VL  - 18
IS  - 5, Art. 995
SP  - 1
EP  - 15
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  -