Abstract
BackgroundProlonged angiogenesis inhibition may improve treatment outcome in metastatic colorectal cancer (mCRC) patients. However, due to the complexity of the angiogenic pathways there is a lack of valid predictive biomarkers for anti-angiogenic agents. Here, we describe and optimize a procedure for simultaneous dynamic profiling of multiple angiogenesis related proteins in patient serum to explore associations with the response and acquired resistance to anti-angiogenic therapy.Materials and methodsPatients (n=22) were selected from a clinical trial investigating maintenance treatment with bevacizumab alone after response to induction chemotherapy + bevacizumab in mCRC. Serum samples were analysed for 55 unique angiogenesis related proteins using a commercial proteome profiler array and a publicly available image analysis program for quantification. Samples were collected at baseline before induction treatment start, at start of maintenance treatment, and at end of treatment after tumour progression.Main results and conclusionFor eight proteins, the antibody array signals were below detection range in all patient samples. None of the proteins showed levels at baseline or at start of maintenance with strong evidence for correlation to time to progression (lowest nominal p-value 0.03). The dynamic ranges of protein levels measured during the induction treatment period and during the maintenance period were analysed separately for time trends. Evidence for changing trends (up/down) in the levels of MMP-8, TIMP-4 and EGF was observed both during response to induction treatment and at progressive disease, respectively. For three of the proteins (IL-8, Activin A and IGFBP-2), weak evidence for correlation between increasing protein levels during induction with chemotherapy and bevacizumab and time to progression was observed.In conclusion, semi-quantitative profiling of angiogenesis related proteins in patient serum may be a versatile tool to screen for protein patterns aiming at identifying resistance mechanisms of anti-angiogenic treatment in patients with mCRC.
Highlights
Over four decades ago angiogenesis inhibition was proposed as a strategy to treat cancer [1], and since several therapeutic compounds targeting angiogenesis have been introduced
We explore a commercially available antibody protein array for the simultaneous assessment of 55 different angiogenesis related proteins in serially collected serum samples from metastatic colorectal cancer (mCRC) patients selected from a randomized clinical trial investigating induction chemotherapy with bevacizumab followed by maintenance single bevacizumab until tumour progression
We selected patients that had at least stable disease on induction treatment, who were randomized to single bevacizumab maintenance treatment, and who had progressive disease (PD) as reason for end of treatment (EOT) (Fig 1)
Summary
Over four decades ago angiogenesis inhibition was proposed as a strategy to treat cancer [1], and since several therapeutic compounds targeting angiogenesis have been introduced. These agents, which have played an important role in both oncological research and clinical practice, include small molecule tyrosine kinase inhibitors and antibodies targeting e.g. the vascular endothelial growth factor (VEGF) receptors and its ligands. Some patients benefit by a prolonged inhibition of angiogenesis in the continuum of care, as demonstrated in mCRC trials by anti-angiogenic antibody addition to chemotherapy beyond progression [4,5,6]. We describe and optimize a procedure for simultaneous dynamic profiling of multiple angiogenesis related proteins in patient serum to explore associations with the response and acquired resistance to anti-angiogenic therapy
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