title: Novel TIE-2 inhibitor BAY-826 displays in vivo efficacy in experimental syngeneic murine glioma models.
abstract: Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3VO4-induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models (SMA-497 and SMA-540) and there was a significant survival benefit in one model (SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model (SMA-497), but provided synergistic prolongation of survival in another (SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.
authors: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Hannah
authors: H
authors: Schneider
authors: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Emese
authors: E
authors: Szabo
authors: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
authors: Raquel A C
authors: RA
authors: Machado
authors: Laboratory for Molecular Radiobiology, Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.
authors: Angela
authors: A
authors: Broggini-Tenzer
authors: GTRG Oncology II, Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors: Alexander
authors: A
authors: Walter
authors: Medicinal Chemistry, Drug Discovery, Bayer Pharma AG, Wuppertal, Germany.
authors: Mario
authors: M
authors: Lobell
authors: GTRG Oncology II, Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors: Dieter
authors: D
authors: Heldmann
authors: Medicinal Chemistry, Drug Discovery, Bayer Pharma AG, Wuppertal, Germany.
authors: Frank
authors: F
authors: Süssmeier
authors: GTRG Oncology II, Drug Discovery, Bayer Pharma AG, Berlin, Germany.
authors: Sylvia
authors: S
authors: Grünewald
authors: Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.|Center for Neuroscience, University of Zurich, Zurich, Switzerland.
authors: Michael
authors: M
authors: Weller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology*; D064596:Isografts; D051379:Mice; D008810:Mice, Inbred C57BL; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
keywords: BAY-826; TIE-2 inhibition; glioma; irradiation; syngeneic