Biomarker and histopathology evaluation of patients with recurrent glioblastoma treated with galunisertib, lomustine, or the combination of galunisertib and lomustine

• Verfasst von: Capper, David [VerfasserIn]
• Verfasst von: Deimling, Andreas von [VerfasserIn]
• Verfasst von: Wick, Wolfgang [VerfasserIn]
• Titel: Biomarker and histopathology evaluation of patients with recurrent glioblastoma treated with galunisertib, lomustine, or the combination of galunisertib and lomustine
• Verf.angabe: David Capper, Andreas von Deimling, Alba A. Brandes, Antoine F. Carpentier, Santosh Kesari, Juan M. Sepulveda-Sanchez, Helen R. Wheeler, Olivier Chinot, Lawrence Cher, Joachim P. Steinbach, Pol Specenier, Jordi Rodon, Ann Cleverly, Claire Smith, Ivelina Gueorguieva, Colin Miles, Susan C. Guba, Durisala Desaiah, Shawn T. Estrem, Michael M. Lahn, Wolfgang Wick
• E-Jahr: 2017
• Jahr: 6 May 2017
• Umfang: 15 S.
• Teil: volume:18
• Teil: year:2017
• Teil: number:5
• Teil: pages:1-15
• Teil: extent:15
• Fussnoten: Gesehen am 19.04.2018
• Titel Quelle: Enthalten in: International journal of molecular sciences
• Ort Quelle: Basel : Molecular Diversity Preservation International, 2000
• Jahr Quelle: 2017
• Band/Heft Quelle: 18(2017,5) Artikel-Nummer 995, 15 Seiten
• ISSN Quelle: 1422-0067
• ISSN Quelle: 1661-6596
• DOI: doi:10.3390/ijms18050995
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: biomarkers
• Sach-SW: CDK4/CDK6
• Sach-SW: galunisertib monohydrate (LY2157299)
• Sach-SW: pSMAD2
• Sach-SW: TGF-β
• K10plus-PPN: 1572153741

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.