title: Targeted Proteomics to Assess the Response to Anti-Angiogenic Treatment in Human Glioblastoma (GBM).
abstract: Glioblastoma (GBM) is a highly aggressive primary brain tumor with dismal outcome for affected patients. Because of the significant neo-angiogenesis exhibited by GBMs, anti-angiogenic therapies have been intensively evaluated during the past years. Recent clinical studies were however disappointing, although a subpopulation of patients may benefit from such treatment. We have previously shown that anti-angiogenic targeting in GBM increases hypoxia and leads to a metabolic adaptation toward glycolysis, suggesting that combination treatments also targeting the glycolytic phenotype may be effective in GBM patients. The aim of this study was to identify marker proteins that are altered by treatment and may serve as a short term readout of anti-angiogenic therapy. Ultimately such proteins could be tested as markers of efficacy able to identify patient subpopulations responsive to the treatment. We applied a proteomics approach based on selected reaction monitoring (SRM) to precisely quantify targeted protein candidates, selected from pathways related to metabolism, apoptosis and angiogenesis. The workflow was developed in the context of patient-derived intracranial GBM xenografts developed in rodents and ensured the specific identification of human tumor versus rodent stroma-derived proteins. Quality control experiments were applied to assess sample heterogeneity and reproducibility of SRM assays at different levels. The data demonstrate that tumor specific proteins can be precisely quantified within complex biological samples, reliably identifying small concentration differences induced by the treatment. In line with previous work, we identified decreased levels of TCA cycle enzymes, including isocitrate dehydrogenase, whereas malectin, calnexin, and lactate dehydrogenase A were augmented after treatment. We propose the most responsive proteins of our subset as potential novel biomarkers to assess treatment response after anti-angiogenic therapy that warrant future analysis in clinical GBM samples.
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Kevin
authors.initials: K
authors.lastname: Demeure
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Fred
authors.initials: F
authors.lastname: Fack
authors.affiliation: §Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Elodie
authors.initials: E
authors.lastname: Duriez
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Katja
authors.initials: K
authors.lastname: Tiemann
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Amandine
authors.initials: A
authors.lastname: Bernard
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Anna
authors.initials: A
authors.lastname: Golebiewska
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bougnaud
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; ¶KG Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.affiliation: §Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Bruno
authors.initials: B
authors.lastname: Domon
authors.affiliation: From the ‡NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; ¶KG Jebsen Brain Tumour Research Center, Department of Biomedicine, University of Bergen, Bergen, Norway simone.niclou@lih.lu.
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D040901:Proteomics; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000068258:Bevacizumab