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Title: Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine.
Austin Authors: Capper, David;von Deimling, Andreas;Brandes, Alba A;Carpentier, Antoine F;Kesari, Santosh;Sepulveda-Sanchez, Juan M;Wheeler, Helen R;Chinot, Olivier;Cher, Lawrence M ;Steinbach, Joachim P;Specenier, Pol;Rodon, Jordi;Cleverly, Ann;Smith, Claire;Gueorguieva, Ivelina;Miles, Colin;Guba, Susan C;Desaiah, Durisala;Estrem, Shawn T;Lahn, Michael M;Wick, Wolfgang
Affiliation: Department of Neuropathology, Charité Universitätsmedizin Berlin, Berlin, Germany
Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Medical Oncology Department, Bellaria-Maggiore Hospitals, Azienda USL-IRCCS Institute of Neurological Sciences, Bologna, Italy
Assistance Publique-Hôpitaux de Paris (AP-HP) & Paris 13 University, Hôpital Avicenne, Service de Neurologie, Bobigny, France
UC San Diego Health System, La Jolla, CA, USA
Hospital Universitario 12 de Octubre, Madrid, Spain
Department of Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia
CHU Hôpital De La Timone, Rue Saint Pierre, Marseille, France
Austin Health, Heidelberg, Victoria, Australia
Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Frankfurt, Germany
Antwerp University Hospital, Edegem, Belgium
Medical Oncology, Vall d'Hebron University Hospital, Calle Natzaret, Barcelona, Spain
Eli Lilly and Company, Erl Wood Manor, Windlesham, UK
Eli Lilly and Company, Indianapolis, IN, USA
Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
Issue Date: 6-May-2017 2017-05-06
Publication information: International journal of molecular sciences 2017; 18(5): e995
Abstract: 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.
DOI: 10.3390/ijms18050995
PubMed URL: 28481241
Type: Journal Article
Subjects: CDK4/CDK6
galunisertib monohydrate (LY2157299)
Appears in Collections:Journal articles

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