Download LIBACS_Hull_Volpato - Faculty of Medicine and Health

PhD Studentship in the Leeds Institute of Biomedical and Clinical
Sciences
Faculty of Medicine and Health
University of Leeds
Can an orphan G-couple protein receptor be key in improving colorectal cancer
patient response to EPA and personalising therapy?
Supervisors: Professor Mark Hull, Dr Milene Volpato
Funding: LIBACS, Leeds NHS Trust Charitable Fund
A PhD studentship is available for UK and EU citizens only. The studentship will attract an
annual tax-free stipend of £14,420 for up to 3 years, subject to satisfactory progress and will
cover the UK/EU tuition fees.
You should hold a first degree equivalent to at least a UK upper second class honours
degree in a relevant subject. This project would suit a student with a strong background
cellular and molecular biology.
Candidate whose first language is not English must provide evidence that their English
language is sufficient to meet the specific demands of their study, the Faculty minimum
requirements are:
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British Council IELTS - score of 6.5 overall, with no element less than 6.0
TOEFL iBT - overall score of 92 with the listening and reading element no less than
21, writing element no less than 22 and the speaking element no less than 23.
Research Project:
Colorectal cancer is the third most common cancer in the UK. Approximately one third of CRC
patients develop liver metastasis within 5 years. Only one quarter of these are suitable for
resection surgery, which remains the only curative therapy. Currently, there is no effective
medical therapy for prevention or treatment of CRC liver metastases.
The long-chain (>20 carbon) omega-3 fatty acids (O3FAs) eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) are present naturally in oily fish. Vast clinical experience of
purified O3FAs in pharmaceutical form in cardiology patients has confirmed their excellent
safety and tolerability profile. The promise of O3FAs for prevention of colorectal cancer (CRC),
suggested by epidemiological studies over several decades, has now begun to be realise with
proof from a Leeds trial (ClinicalTrials.gov NCT00510692) that oral EPA 2 g daily has
chemopreventative efficacy in familial adenomatous polyposis (1) and with ongoing evaluation
of EPA in the seAFOod Polyp Prevention Trial (ISRCTN05926847; CI Professor Hull).
Pre-clinical studies have also highlighted that O3FAs have direct anti-CRC activity (2-4). This
prompted us to evaluate the same dose of EPA for neo-adjuvant treatment of CRC liver
metastasis (CRCLM) patients undergoing liver resection in a randomised controlled trial (the
EMT study; ClinicalTrials.gov NCT01070355). Remarkably, short-term dosing (median 30
days) conferred overall survival (OS) benefit for 12-18 months after surgery (5).
In parallel to RCTs, the Hull laboratory has continued to explore the mechanistic basis of the
anti-CRC activity of EPA. We have established two syngeneic mouse CRC tumour models
and isogenic CRC cell lines with varying sensitivity to EPA. Using these CRC cell models, we
performed two complementary whole genome expression microarrays in order to identify
genes that may have a role in mediating cancer cell response and/or resistance to EPA.
Several exciting novel gene targets with potential as a new anti-cancer target have emerged
from these screens. We are currently focusing our efforts on validation of the most relevant
and exciting of these target genes (a G protein-coupled receptor) based on its potential as a
clinical biomarker and/or target for other novel anti-cancer therapy. Study of this orphan Gprotein coupled receptor (GPCR) will be the focus of the project.
The aim of this research project is to investigate the expression and function of the GPCR as
a predictive biomarker of response to EPA and as an anti-cancer target per se. The student
will examine the effect of siRNA ‘knockdown’ of the gene on EPA sensitivity of CRC and other
cell lines. The student will use stable overexpressing cell line models in order to build further
the scientific case for detailed pharmacological work-up of the gene target. Other candidate
genes identified in the screen may be studied during this project. The data will form a platform
for the identification and validation of potential predictive marker in clinical samples in order to
build further the scientific case for use of O3FAs in the clinic. The student will use a wide range
of molecular and cellular biology techniques such as cell culture, immunofluorescence,
confocal imaging, immunohistochemistry and western blotting as necessary. Fatty acid
incorporation and prostaglandin metabolism may also be investigated using established LCESI-MS/MS protocols.
1.
West NJ, Clark SK, Phillips RK, Hutchinson JM, Leicester RJ, Belluzzi A, et al.
Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous
polyposis. Gut. 2010;59(7):918-25.
2.
Hawcroft G, Loadman PM, Belluzzi A, Hull MA. Effect of eicosapentaenoic acid on Etype prostaglandin synthesis and EP4 receptor signaling in human colorectal cancer cells.
Neoplasia. 2010;12(8):618-27.
3.
Hawcroft G, Volpato M, Marston G, Ingram N, Perry SL, Cockbain AJ, et al. The
omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal
cancer cell liver metastasis via inhibition of PGE2-dependent cell motility. British journal of
pharmacology. 2012;166(5):1724-37.
4.
Volpato M, Perry SL, Marston G, Ingram N, Cockbain AJ, Burghel H, et al. Changes in
plasma chemokine C-C motif ligand 2 levels during treatment with eicosapentaenoic acid
predict outcome in patients undergoing surgery for colorectal cancer liver metastasis.
Oncotarget. 2016.
5.
Cockbain AJ, Volpato M, Race AD, Munarini A, Fazio C, Belluzzi A, et al. Anticolorectal
cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid. Gut.
2014;63(11):1760-8.
Environment:
The successful candidate will join a multidisciplinary team of research fellows, research
assistant and PhD/MD students with expertise ranging from cancer pharmacology and cell
biology to molecular imaging and nanotechnology. The student will be based in the University
of Leeds in the Section of Molecular Gastroenterology, Leeds Institute of Biomedical and
Clinical Sciences. Training will be provided in the relevant technical areas. Attendance to
training courses specifically aimed at postgraduate research student will be strongly
encouraged. The research group actively collaborates with other teams led by Dr Coletta in
Leeds, Prof Loadman at the ICT in Bradford), Dr Zelenay in Manchester and Prof Phillips in
Huddersfield.
How to apply:
To apply for this scholarship applicants should complete a Faculty Scholarship Application
form and send this alongside a full academic CV, degree transcripts (or marks so far if still
studying) and degree certificates to the Faculty Graduate School [email protected]
We also require 2 academic references to support your application. Please ask your referees
to send these references on your behalf, directly to [email protected] by no later than
Friday 27 January 2017.
Any queries regarding the application process should be directed to [email protected] .
For further information on the project please direct your queries to Dr Volpato
[email protected]
Closing date for this studentship is Friday 27 January 2017