title: TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors.
abstract: ASA404 (Vadimezan) belongs to a class of agents with disrupting properties against tumor vasculature, which is partly mediated by TNFα-signaling. Preclinical and early clinical studies have indicated promising results for ASA404, while extended clinical trials performed poorly. Our aim was to investigate the potential therapeutic applicability of ASA404 against endocrine tumors. Moreover, as the reason for the unpredictable clinical anti-tumor activity of ASA 404 remained uncertain in previous studies, we compared two tumor models of endocrine origin with different responses to ASA404 treatment. Specifically, we determined anti-tumoral effects in preclinical models of neuroendocrine tumors of the gastroenteropancreatic system (BON) and adrenocortical cancer (NCI-H295R) in vitro and in xenograft models in vivo. Upon treatment of tumor bearing mice significant anti-tumoral effects, an increase in TNFα as well as activation of TNFα-specific downstream signaling were evident in the BON tumor model while no comparable effects were detectable for NCI-H295R. We identified TNFAIP3/A20, a key molecule of an inhibitory feedback-loop downstream of TNF-receptor 1, CD40, Toll-like receptors, NOD-like receptors and the interleukin-1 receptor signaling cascades, as overexpressed in the adrenocortical carcinoma tumor model. Subsequent analyses of clinical patient samples confirmed a correlation between tumor TNFAIP3 expression levels and overall survival in patients with ACC. Taken together our findings provide evidence that modulation of TNFα-signaling could be of relevance both for the clinical course of ACC patients and as a marker of treatment response.
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany. Electronic address: Constanze.Hantel@med.uni-muenchen.de.
authors.forename: Constanze
authors.initials: C
authors.lastname: Hantel
authors.affiliation: Department of Surgery, Klinikum der Universität München, Munich, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ozimek
authors.affiliation: Pediatrics Department, FMRP-USP, Ribeirão Preto, Brazil.
authors.forename: Regia
authors.initials: R
authors.lastname: Lira
authors.affiliation: Institut Cochin, Inserm U1016, Cnrs UMR8104, Université Paris Descartes, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: Clinical Biochemistry, Medizinische Klinik und Poliklinik IV, Munich, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Jäckel
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Frantsev
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.affiliation: Institut Cochin, Inserm U1016, Cnrs UMR8104, Université Paris Descartes, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: Department of Surgery, Klinikum der Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mussack
authors.affiliation: Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D016016:Proportional Hazards Models; D015398:Signal Transduction; D015533:Transcriptional Activation; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D044004:Xanthones / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan; D053592:Interleukin-1 Receptor-Associated Kinases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D017239:Paclitaxel
keywords: Endocrine tumors; TNFAIP3/A20; TNFα; Tumor-Vascular-Disrupting-Agent