Current Research Projects
Funded by the MRC, Wellcome Trust, and the Society for Endocrinology, our current research projects focus on investigating oestrogen action in colorectal cancer, understanding the role of NNT in adrenal adenocarcinoma, and mining the cancer metabolome to identify novel therapeutic targets
Oestrogen & Colorectal Cancer
Funding: MRC PhD, Society for Endocrinology
It is a well documented fact (see here and here) that pre-menopausal women, or those on hormone replacement therapy, are significantly less likely to develop colorectal cancer compared to aged-matched men. This strongly implies a role for oestrogens in this malignancy. Interestingly, although initially protective, there is a growing body of evidence that suggests oestrogens are involved in the proliferation of colorectal cancer once this malignancy has established (see here, here, and here). However, there remains a lack of understanding on the molecular mechanisms that may be inveolved in this process
We are currently investigating the role oestrogens play in colorectal cancer protection and development (see our recent review article here). Our studies have identified that human colorectal cancer tissue has a elevated ability to active local oestrogens. From these clinical studies, we are creating novel cellular and animal models that mimic the human disease, therefore providing us with a unique platform from which to directly study the importance of oestrogens and thie metabolism in colorectal cancer. Our results will clarify whether oestrogen administration or modulators may be effective at treating this aggressive malignancy.
NNT in Adrenocortical Cancer
Funding: Wellcome Trust
Adrenocortical carcinoma (ACC) is a rare cancer (annual incidence 1 per million population) with poor prognosis (overall 5-year survival 20-60%). Approximately 50% of patients initially present or recur with metastatic disease, which usually precludes surgical treatment and carries a dismal outlook (5-year survival <15%). Unfortunately, little progress has been achieved in the management of patients with advanced ACC. Therefore, novel drugs with targeted anti-cancer activity in ACC are urgently needed.
We are currently investigating the role of nicotinamide nucleotide transhydrogenase (NNT) in ACC. A recent study has identified inactivating NNT mutation in patients presenting with a phenotype of Familial Glucocorticoid Deficiency. Of note, except for isolated glucocorticoid deficiency, the affected patients did not show any other abnormalities. This suggests a selectively increased susceptibility of adrenal cells to NNT inactivation, resulting in disruption of steroidogenesis and increased apoptosis.
Mining the Cancer Metabolome
Funding: ISSF Wellcome Trust
Recent groundbreaking research implements the cancer metabolome in apoptotic resistance. Taxane treatment, a common clinical anti-cancer strategy, may alter cancer cell metabolism, up-regulating specific metabolic pathways leading to chemotherapeutic resistance. Intriguingly, we have shown that metabolic inhibition synergises with taxane treatment in vitro and with microtubule targeted compounds in vivo to augment cancer apoptosis. We are therefore investigating the taxane-induced metabolomic changes that are amenable to further therapeutic intervention. However, at present, there lacks clarity on how taxanes alter metabolomic pathways within cancer. Consequently, exactly which metabolite pathways should be targeted remains unknown. Therefore, we are currently:-
1) Identify taxane-induced metabolomic pathway shifts amenable to therapeutic intervention.
2) Pharmacologcally target these metabolomic shifts to augment taxane-induced apoptosis.
PDI as a novel target against ovarian cancer
Overcoming chemo-resistance in ovarian cancer is a major clinical challenge, and identifying new therapies that target chemo-resistance is of significant importance. The endoplasmic reticulum (ER) enzyme, protein disulfide isomerase (PDI), regulates cellular proteostasis, disruption of which causes ER-stress and, ultimately, apoptosis. PDI also plays a critical role in chemo-resistance in cancer. Therefore, targeting PDI may not only be a successful mono-therapeutic strategy, but may also re-sensitise ovarian cancer to chemotherapy.
We have identified a novel compound, XCE853, that potently inhibits PDI activity and exhibits increased efficacy in chemo-resistant, compared to chemo-naive, ovarian cancer. In cellular models, XCE853 co-localises with PDI and also shows significant efficacy in an ovarian cancer xenograft (OVCAR-3) mouse model. Collaborating with both academic leads in the UK and USA and with industrial partners, we are furthering our investigations on PDI and its role in chemo-resistance in ovarian cancer.