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    Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways

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    11
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    Author
    Greening, DW; Lee, ST; Ji, H; Simpson, RJ; Rigopoulos, A; Murone, C; Fang, C; Gong, S; O'Keefe, G; Scott, AM
    Date
    2015-11-10
    Source Title
    Oncotarget
    Publisher
    IMPACT JOURNALS LLC
    University of Melbourne Author/s
    Scott, Andrew; O'Keefe, Graeme
    Affiliation
    Medicine and Radiology
    School of Physics
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Greening, D. W., Lee, S. T., Ji, H., Simpson, R. J., Rigopoulos, A., Murone, C., Fang, C., Gong, S., O'Keefe, G. & Scott, A. M. (2015). Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways. ONCOTARGET, 6 (35), pp.38166-38180. https://doi.org/10.18632/oncotarget.6241.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257739
    DOI
    10.18632/oncotarget.6241
    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.

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