• Blockade of platelet-derived growth factor receptor-beta by CDP860, a humanized, PEGylated di-Fab', leads to fluid accumulation and is associated with increased tumor vascularized volume.

      Jayson, Gordon C; Parker, Geoff J M; Mullamitha, Saifee A; Valle, Juan W; Saunders, Mark P; Broughton, Lynn; Lawrance, Jeremy A L; Carrington, Bernadette M; Roberts, Caleb; Issa, B; et al. (2005-02-10)
      PURPOSE: CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-beta). Studies in animals have suggested that PDGFR-beta inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. PATIENTS AND METHODS: Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. RESULTS: Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. CONCLUSION: These observations suggest that inhibition of PDGFR-beta might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.
    • Identification of early predictive imaging biomarkers and their relationship to serological angiogenic markers in patients with ovarian cancer with residual disease following cytotoxic therapy.

      Mitchell, Claire L; O'Connor, James P B; Jackson, A; Parker, G J M; Roberts, C; Watson, Y; Cheung, S; Davies, K; Buonaccorsi, G A; Clamp, Andrew R; et al. (2010-03-29)
      BACKGROUND: Patients with recurrent ovarian cancer often achieve partial response following chemotherapy, resulting in persistent small volume disease. After completion of treatment, the dilemma of when to initiate subsequent chemotherapy arises. Identification of biomarkers that could be used to predict when subsequent treatment is needed would be of significant benefit. Design: Twenty-three patients with advanced ovarian cancer and residual asymptomatic disease following chemotherapy underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at study entry, 4, 8, 12, 18 and 26 weeks or disease progression. A subgroup of patients provided plasma samples within which a panel of angiogenic biomarkers was quantified. RESULTS: By 4 weeks, significant differences in whole tumour volume, enhancing fraction and Ca125 were observed between patients whose disease progressed by 26 weeks and those who remained stable. Significant correlations between plasma soluble vascular endothelial growth factor recptor-1 (sVEGFR-1) and sVEGFR-2 concentrations, and blood volume and tumour endothelial permeability surface area product measured by DCE-MRI were observed. CONCLUSIONS: Imaging markers have a potential role in early prediction of disease progression in patients with residual ovarian cancer and may supplement current measures of progression. The correlation of DCE-MRI and serological biomarkers suggests that tumour angiogenesis affects these markers through common biological means and warrants further investigation.
    • Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma.

      Linnik, I V; Scott, M L J; Holliday, K F; Woodhouse, N l; Waterton, J C; O'Connor, James P B; Barjat, H; Liess, C; Ulloa, J; Young, H; et al. (2014-05)
      There is a clinical need for noninvasive, nonionizing imaging biomarkers of tumor hypoxia and oxygenation. We evaluated the relationship of T1 -weighted oxygen-enhanced magnetic resonance imaging (OE-MRI) measurements to histopathology measurements of tumor hypoxia in a murine glioma xenograft and demonstrated technique translation in human glioblastoma multiforme.
    • Oxygen enhanced MRI accurately identifies, quantifies, and maps hypoxia in preclinical cancer models.

      O'Connor, James P B; Boult, J; Jamin, Y; Babur, M; Finegan, K; Williams, K; Little, R; Jackson, A; Parker, G; Reynolds, A; et al. (2015-12-09)
      There is a clinical need for non-invasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning and therapy monitoring. Oxygen enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (∆R1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ∆R1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ∆R1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here we demonstrate that OE-MRI signals are accurate, precise and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia non-invasively and is immediately translatable to the clinic.
    • Radiotherapy in the management of unresectable locally advanced pancreatic cancer: a survey of the current UK practice of clinical oncologists.

      Saleem, Azeem; Jackson, A; Mukherjee, S; Stones, N; Crosby, T; Tait, D; Price, Patricia M; University of Manchester Academic Radiation Oncology, The Christie NHS Foundation Trust, Manchester, UK. azeem.saleem@manchester.ac.uk (2010-05)
      A survey was conducted by the Academic Clinical Oncology and Radiobiology Research Network (ACORRN) to evaluate current radiotherapy practice and to inform future research needs in patients with locally advanced pancreatic cancer. A clear need for a co-ordinated multicentre approach, given the limited number of patients who may qualify for such UK trials, was identified. Such trials should incorporate evidence-based treatment protocols and appropriate quality assurance procedures to ensure delivery of the highest standards of radiation-based therapy within, and without, clinical trials.