title: Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways.
abstract: Angiogenesis and epidermal growth factor receptor (EGFR) inhibition has been shown to have anti-tumour efficacy, and enhance the therapeutic effects of cytotoxic chemotherapy in metastatic colorectal cancer. The interplay of signalling alterations and changes in metabolism and hypoxia in tumours following anti-VEGF and anti-EGFR treatment is not well understood. We aimed to explore the pharmacodynamics of cetuximab and bevacizumab treatment in human colon carcinoma tumour cells in vitro and xenograft models through proteomic profiling, molecular imaging of metabolism and hypoxia, and evaluation of therapy-induced changes in tumour cells and the tumour microenvironment. Both cetuximab and bevacizumab inhibited tumour growth in vivo, and this effect was associated with selectively perturbed glucose metabolism and reduced hypoxic volumes based on PET/MRI imaging. Global proteomic profiling of xenograft tumours (in presence of cetuximab, bevacizumab, and combination treatments) revealed alterations in proteins involved in glucose, lipid and fatty acid metabolism (e.g., GPD2, ATP5B, STAT3, FASN), as well as hypoxic regulators and vasculogenesis (e.g., ATP5B, THBS1, HSPG2). These findings correlated with western immunoblotting (xenograft lysates) and histological examination by immunohistochemistry. These results define important mechanistic insight into the dynamic changes in metabolic and hypoxic response pathways in colorectal tumours following treatment with cetuximab and bevacizumab, and highlight the ability of these therapies to selectively impact on tumour cells and extracellular microenvironment.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Greening
authors.affiliation: Department of Molecular Imaging and Therapy, University of Melbourne, Austin Hospital, Melbourne, Australia.|Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Sze Ting
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Simpson
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Rigopoulos
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Carmel
authors.initials: C
authors.lastname: Murone
authors.affiliation: Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fang
authors.affiliation: Department of Molecular Imaging and Therapy, University of Melbourne, Austin Hospital, Melbourne, Australia.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Gong
authors.affiliation: Department of Molecular Imaging and Therapy, University of Melbourne, Austin Hospital, Melbourne, Australia.|Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Graeme
authors.initials: G
authors.lastname: O'Keefe
authors.affiliation: Department of Molecular Imaging and Therapy, University of Melbourne, Austin Hospital, Melbourne, Australia.|Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia.|School of Cancer Medicine, La Trobe University, Melbourne, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D000068258:Bevacizumab; D000068818:Cetuximab
keywords: bevacizumab; cancer therapeutics; cetuximab; hypoxia; metabolism