title: The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer.
abstract: BNC105 is a tubulin targeting compound that selectively disrupts vasculature within solid tumors. The severe tumor hypoxia and necrosis that ensues translates to short term tumor growth inhibition. We sought to identify the molecular and cellular events activated following BNC105 treatment that drives tumor recovery. We investigated tumor adaptation to BNC105-induced hypoxia in animal models of breast and renal cancer. HIF-1α and GLUT-1 were found to be strongly upregulated by BNC105 as was the VEGF signaling axis. Phosphorylation of mTOR, 4E-BP-1 and elF2α were upregulated, consistent with increased protein synthesis and increased expression of VEGF-A. We sought to investigate the potential therapeutic utility of combining BNC105 with agents targeting VEGF and mTOR signaling. Bevacizumab and pazopanib target the VEGF axis and have been approved for first line use in renal cancer. Everolimus targets mTOR and is currently approved in second line therapy of renal and particular breast cancers. We combined these agents with BNC105 to explore the effects on tumor vasculature, tumor growth inhibition and animal survival. Bevacizumab hindered tumor vascular recovery following BNC105 treatment leading to greater tumor growth inhibition in a breast cancer model. Consistent with this, addition of BNC105 to pazopanib treatment resulted in a significant increase in survival in an orthotopic renal cancer model. Combination treatment of BNC105 with everolimus also increased tumor growth inhibition. BNC105 is currently being evaluated in a randomized phase II clinical trial in combination with everolimus in renal cancer.
authors.affiliation: a Bionomics Ltd. ; Thebarton , South Australia , Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Inglis
authors.forename: Tina C
authors.initials: TC
authors.lastname: Lavranos
authors.forename: Donna M
authors.initials: DM
authors.lastname: Beaumont
authors.forename: Annabell F
authors.initials: AF
authors.lastname: Leske
authors.forename: Chloe K
authors.initials: CK
authors.lastname: Brown
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Hall
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kremmidiotis
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000840:Anisoles; D000970:Antineoplastic Agents; C552092:BNC 105; D001572:Benzofurans; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D058570:TOR Serine-Threonine Kinases
keywords: 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; GLUT-1, glucose transporter 1; H&E, hematoxylin and eosin.; HIF1α, hypoxia-inducible factor 1-alpha; IFNα, interferon α; NSCLC, non-small-cell lung carcinoma; PDGFR, platelet-derived growth factor receptor; PERK, protein kinase-like endoplasmic reticulum kinase; PFS, progression free survival; TKI, tyrosine kinase inhibitor; VDA, vascular disrupting agent; VEGF; VEGF, vascular endothelial growth factor; breast; eIF2a, eukaryotic translation initiation factor 2a; hypoxia; mTOR; mTOR, mammalian target of rapamycin; renal