Title: Antibody-based VEGF receptor 2 inhibition (DC101)in combination with radiotherapy: influence of VEGF isoforms and related microenvironmental factors
Funder: Cancer Research UK

Abstract: Vascular endothelial growth factor-A (VEGF) pathway inhibitors have shown efficacy in a number of cancer disease settings, especially in combination with conventional treatment. However, response is variable and there is a recognized need for predictive biomarkers of tumour response to optimize use of these agents. Ramucirumab (a Lilly compound) is a fully humanized VEGF receptor-2 blocking antibody in late-stage clinical trial and under FDA priority review. Its approval is awaited with anticipation, as it will be the most specific VEGFR-2 inhibitor available for clinical practice. The anti-mouse VEGF equivalent of ramucirumab is DC101. There is a strong rationale for combining ramucirumab with radiotherapy, based on pre-clinical evidence for VEGF pathway inhibitors normalizing the tumour microcirculation (thus improving oxygenation) and radiosensitising endothelial cells, as well as radiation stimulating VEGF production. However, response is variable here too. Differential VEGF isoform expression and/or markers of their influence on the tumour microenvironment are potential predictive biomarkers for tumour response to the combination of DC101 with radiotherapy. Specifically, we have found that tumours expressing only the VEGF188 isoform, are particularly sensitive to both treatments, as single agents. Therefore, we hypothesise that the combination treatment will be correspondingly effective in tumours influenced by VEGF188. The primary aim of the study is to determine the efficacy of combining DC101 with radiotherapy, in mouse fibrosarcomas that differentially express single VEGF isoforms The secondary aim is to identify treatment-induced changes in immuno-histochemical markers of VEGF isoform expression in the same cohort. Mouse fibrosarcoma cells developed to express only VEGF120 (fs120), VEGF164 (fs164), VEGF188 (fs188) or all isoforms (fsWT) and expressing luciferase will be used. DC101 will be supplied by Imclone Systems/Lilly. Tumour growth delay will be used to measure treatment response to fractionated radiotherapy ± DC101 and lung metastasis will be measured at the end of treatment using optical imaging and histology. Immunohistochemical analysis of excised tumours for hypoxia and vascularity will be carried out during and after treatment. If, as expected, the combination of radiotherapy and DC101 is most effective in fs188 tumours, this would support a clinical trial of ramucirumab with radiotherapy in soft-tissue sarcoma, incorporating a translational arm investigating the differential tumour expression of VEGF isoforms and their down-stream effects on the tumour microenvironment. Ultimately, this could lead to identification of much sought-after predictive bio-markers for selection of cancer patients for vascular-targeted treatment in combination with conventional therapy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS