Research Themes
Endocrinology, Oncology, Oestrogen Metabolism, Colorectal Cancer, Breast Cancer, Metabolic inhibitors, Novel in vivo Cancer Modelling.
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Oestrogens in colorectal cancer
Uncertainty surrounds the actions of oestrogens in colorectal cancers (CRC). Although epidemiological evidence suggests that oestrogens are protective against this malignancy, there is now significant research demonstrating that oestrogen action may increase the incidence and proliferation of colorectal cancer. What is clear is that the regulation of oestrogen synthesis and metabolism is important in CRC. Numerous studies indicate that oestrogen receptor (ER, which when activated induces apoptosis, is lost during colonic tumourigenesis. We have shown that steroid sulphatase (STS), which desulphated conjugated oestrogens to their active forms, is elevated in CRC, and therefore active oestrogens may be involved in colorectal cancer development. Down-regulation of 17-HSD-2, which oxidises oestradiol (E2) to E1, has also been shown to be a negative prognostic factor for CRC mortality, and the ratio between STS and sulphotransferase (SULT1E1), enzymes that de-sulphate and sulphate E1 respectively, is a potent prognostic factor for CRC clinical outcomes.However, much remains unclear due to a lack of basic molecular research. For example, although the STS/EST ratio in CRC patient tissue has implications on mortality, it is unknown how this effects CRC cell growth, E1S/E1/E2 concentrations, and ER/ER expression in vitro and in vivo. Furthermore, complete profiling of oestrogenic enzyme expression and activity, which would allow a greater understanding of local oestrogen concentrations, is lacking in available CRC cell lines and patient samples. This information, once ascertained, would clarify how oestrogens influence CRC, potentially leading to new therapeutic avenues for this disease.
Metabolic inhibitors combined with cytotoxics as anti-cancer treatmentTraditional and novel cytotoxic agents have their efficacy compromised against many cancers due to toxicological complications. Strategies that limit these difficulties without decreasing cytotoxic activity are now important areas of research. One such approach, the combination of glycolytic inhibitors with a lower dose of cytotoxic, has gained significant interest over the past few years. Preliminary research, in breast cancer xenografts, of combining 2-deoxyglucose (2-DG), a glucose analogue that competitively inhibits glycolysis, with an experimental cytotoxic (STX140, Ipsen Pharma. Ltd.), has been positive. A clinical trial investigating 2-DG combination with Taxotere (docetaxel) has also shown some success, and prodrugs of 2-DG are now in development (by Intertech Bio, Houston). Other combinations utilising glycolysis inhibitors (e.g. 2-fluoro-2-deoxy-D-glucose (2-FG), dichloroacetic acid (DCA)), gluconeogenesis inhibitors (e.g. metformin), and cytotoxics (e.g. paclitaxel) remain to be examined. Indeed, DCA, an inhibitor of pyruvate dehydrogenase kinase, has recently moved onto Phase III clinical trials and combinational studies, in order to ascertain this compounds synergistic effects with cytotoxics, are of potential therapeutic interest.