• Biomarkers of angiogenesis and their role in the development of VEGF inhibitors.

      Murukesh, N; Dive, Caroline; Jayson, Gordon C; Department of Medical Oncology, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Cancer Research UK and University of Manchester, Wilmslow Road, Withington, Manchester M20 4BX, UK. (2010-01-05)
      Vascular endothelial growth factor (VEGF) has been confirmed as an important therapeutic target in randomised clinical trials in multiple disease settings. However, the extent to which individual patients benefit from VEGF inhibitors is unclear. If we are to optimise the use of these drugs or develop combination regimens that build on this efficacy, it is critical to identify those patients who are likely to benefit, particularly as these agents can be toxic and are expensive. To this end, biomarkers have been evaluated in tissue, in circulation and by imaging. Consistent drug-induced increases in plasma VEGF-A and blood pressure, as well as reductions in soluble VEGF-R2 and dynamic contrast-enhanced MRI parameters have been reported. In some clinical trials, biomarker changes were statistically significant and associated with clinical end points, but there is considerable heterogeneity between studies that are to some extent attributable to methodological issues. On the basis of observations with these biomarkers, it is now appropriate to conduct detailed prospective studies to define a suite of predictive, pharmacodynamic and surrogate response biomarkers that identify those patients most likely to benefit from and monitor their response to this novel class of drugs.
    • Optimisation of circulating biomarkers of cell death for routine clinical use.

      Greystoke, Alastair; Cummings, Jeffrey; Ward, Timothy H; Simpson, Kathryn L; Renehan, Andrew G; Butt, Fouziah; Moore, David; Gietema, J; Blackhall, Fiona H; Ranson, Malcolm R; et al. (2008-05)
      BACKGROUND: M30 and M65 enzyme-linked immunosorbent assays detect circulating cytokeratin 18 fragments released during caspase-dependent or total cell death, respectively, and have potential as biomarkers in epithelial cancers. While these assays have been validated, their robustness for routine clinical use is unknown. PATIENTS AND METHODS: M30 and M65 were measured in matched serum and plasma samples from 31 lung cancer patients and 18 controls. RESULTS: Time allowable between sample acquisition and processing is critical for assays in clinical use. A 4-h delay in processing at room temperature increased M30 (P < 0.0001), an effect minimised by incubation on ice. M30 and M65 in serum were resistant to processing variations including delays. Serum and plasma measurements correlated well although M30 but not M65 was lower in serum (P < 0.0005). Less variation between duplicate assays was observed in serum. Prolonged storage (-80 degrees C) led to increased M30 (12%, 6 months; 34%, 1 year). Sample dilution in the supplied assay diluent proved non-linear, whereas dilution in donor serum or porcine plasma restored linearity up to a ratio of 1 : 6. CONCLUSION: We present recommendations that improve the reliability of these assays for clinical use and recommend serum as the preferred matrix with data more resistant to variations in collection.