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Int. J. Mol. Sci. 2017, 18(5), 995; doi:10.3390/ijms18050995

Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine

1
Department of Neuropathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
2
Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3
Medical Oncology Department, Bellaria-Maggiore Hospitals, Azienda USL—IRCCS Institute of Neurological Sciences, 40139 Bologna, Italy
4
Assistance Publique-Hôpitaux de Paris (AP-HP) & Paris 13 University, Hôpital Avicenne, Service de Neurologie, 93009 Bobigny, France
5
UC San Diego Health System, La Jolla, CA 92103, USA
6
Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
7
Department of Oncology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
8
CHU Hôpital De La Timone, Rue Saint Pierre, 13385 Marseille, France
9
Austin Hospital, Heidelberg, VIC 3084, Australia
10
Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, 60590 Frankfurt, Germany
11
Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium
12
Medical Oncology, Vall d’Hebron University Hospital, Calle Natzaret, 115-117, 08035 Barcelona, Spain
13
Eli Lilly and Company, Erl Wood Manor, Windlesham GU20 6PH, UK
14
Eli Lilly and Company, Indianapolis, IN 46285, USA
15
Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Sanjay K. Srivastava
Received: 14 March 2017 / Revised: 17 April 2017 / Accepted: 25 April 2017 / Published: 6 May 2017
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
View Full-Text   |   Download PDF [2098 KB, uploaded 6 May 2017]   |  

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. View Full-Text
Keywords: galunisertib monohydrate (LY2157299); TGF-β; pSMAD2; CDK4/CDK6; biomarkers galunisertib monohydrate (LY2157299); TGF-β; pSMAD2; CDK4/CDK6; biomarkers
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Capper, 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.; Lahn, M.M.; Wick, W. Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine. Int. J. Mol. Sci. 2017, 18, 995.

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