Our research focuses on targeting steroid metabolism to identify new therapeutic avenues for breast, prostate, ovarian, and colorectal cancer. With a strong interest in the enzymes (steroid sulphatase, sulphotransferases, 17b-hydroxysteroid dehydrogenases) involved in oestrogen activation, our work has identified numerous compounds that target these pathways and are efficacious in pre-clinical cancer models.
Our research group
The group works using various cut-edge in vitro and in vivo methodologies to investigate the importance of steriodogenesis in endocrine-cancers. Collaborating with many groups both nationally and internationally, we are at the forefront of research on various enzymes, primarily steroid sulphatase and 17 b -hydroxysteroid dehydrogenases, essential to oestrogen and androgen activation and metabolism. We have recently developed novel LC/-MS-MS methods to accurately determine oestrogen metabolism and sulphation. This method will be vital to furthering our understanding of how certain tissue and cancer metabolise oestrogens, and how this is involved in proliferation and apoptosis. Furthermore, we have developed novel cell lines of various malignancies that stably over-express our genes of interest, and we use these to successfully generate new in vivo models of hormone-dependent cancer: these models being important for pre-clinical drug development.
Oestrogen Metabolism in Colorectal Cancer:
A particular focus of the group is to tease out the importance oestrogen (and HRT) has on colorectal cancer proliferation or protection. A long-standing scientific puzzle, oestrogens actions with regards colorectal cancer development still remains to be elucidated. Working closely with Prof. Dion Morton (Cancer Sciences), our initial findings implicate oestrogenic effects as potentially important in female patients, suggesting that anti-hormonal therapy might be effective in this cohort. Furthermore, this also suggests that the male and female colon respond differently to endogenous oestrogen action.
OATP regulation in Cancer:
Sulphated steroids must be transported into cells via organic anion transporter proteins (OATP). There is now much interest in the role these OATPs play in steroid metabolism. Thus, we are currently investigating how these OATPs are regulated in cancer, and whether they represent an encouraging target for pharmaceutical intervention.
Targeting the Cancer Metabolome:
Our other research interests lie with understanding cancer metabolomics in order to inhibit this dysregulated metabolism to augment traditional chemotherapy. Furthermore, recent groundbreaking research implements the cancer metabolome in apoptotic resistance. Our research has shown that metabolic inhibition synergises with chemotherapeutic treatment to elevate cancer cell apoptosis. Consequently, and with collaboration with Dr. Daniel Tennant (Cancer Sciences) and Dr. Warwick Dunn (Biosciences), we are currently investigating whether traditional chemotherapy (paclitaxel, docitaxel) induces metabolomic changes in breast cancer cells, and whether these changes can be targeting to identify novel therapeutic avenues.
Protein Disulfide Isomerase Inhibition: Working with industrial partners (CIPREVO, Oregon Therapeutics), and with external (Prof. Neamati, University of Southern California) and internal (Dr. Gareth Lavery & Dr. Sudha Sunhar) collaborators, we have identified a new compound (XCE853) that inhibits protein disulfide isomerase (PDI), an enzyme involved in proteostasis and increased in various cancers. Importantly, our work shows that blocking PDI is very effective at inducing apoptosis in chemo-resistant cancer cells. PDI-inhibition, a novel therapeutic target, is associated with ER-stress and caspase activation. XCE853 has good efficacy against breast and ovarian xenografts in vivo and a promising early toxicological profile. We have therefore now reached a stage for the early pre-clinical development of this compound.
Foster PA (2013) Oestrogen and colorectal cancer: mechanisms and controversies. Int J Colorectal Dis 28:737-49
Foster PA, Day JM, Tutill HJ, Schmidlin F, Sharland CM, Hargrave JD, Vicker N, Potter BV, Reed MJ and Purohit A (2013) STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model. Endocr Relat Cancer 20:53-64
Purohit A and Foster PA (2012) Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers. J Endocrinol 212:99-110
Leese MP, Jourdan F, Kimberley MR, Cozier GE, Thiyagarajan N, Stengel C, Regis-Lydi S, Foster PA, Newman SP, Acharya KR, Ferrandis E, Purohit A, Reed MJ and Potter BV (2010) Chimeric microtubule disruptors. Chem Commun (Camb) 46:2907-9
Foster PA, Chander SK, Newman SP, Woo LW, Sutcliffe OB, Bubert C, Zhou D, Chen S, Potter BV, Reed MJ and Purohit A (2008) A new therapeutic strategy against hormone-dependent breast cancer: the preclinical development of a dual aromatase and sulfatase inhibitor. Clin Cancer Res 14:6469-77