Understanding and targeting prostaglandin E2 signalling for cancer therapy

Introduction

An opportunity to apply for a funded full-time PhD in the Faculty of Health and Applied Sciences, UWE Bristol. The studentship will be funded by a partnership with Sosei Heptares: Ref 2021-OCT-HAS06.

The expected start date of this studentship is October/November 2021.

The closing date for applications is Sunday 8 August 2021

Studentship details

This is one of two available PhD projects that will be supervised by Dr Alex Greenhough (UWE Bristol) in collaboration with Professor Ann Williams and Dr Emma Vincent (University of Bristol) with funding from industrial partner, Sosei Heptares (Cambridge). The purpose of this project is to investigate the use of novel small molecule drug candidates targeting prostaglandin E2 G protein-coupled receptors (GPCRs) for the prevention and treatment of colorectal cancer, the second most common cause of cancer death in the UK.

Background

The cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway plays key roles in colorectal tumorigenesis and is a bona fide target for cancer therapy. PGE2 signals via four GPCRs termed EP receptors (EP1-4), with EP2 and EP4 mediating PGE2’s cancer promoting functions in the tumour microenvironment. PGE2 signalling drives the activation of oncogenic pathways, increases expression of cancer stem cell markers, suppresses tumour immunity and fuels tumour promoting inflammation — all of which may impact patient responses to existing therapies. Selective pharmacological inhibition of EP2/4 receptors therefore represents an exciting strategy to target PGE2 signalling for cancer prevention and/or as an adjunctive therapy.

Aims

This project will focus on understanding novel mechanisms of PGE2 signalling in the context of EP receptor modulation for cancer prevention and therapy. Specifically, the project will aim to:

  1. define the functional phenotypic consequences of EP receptor genetic loss-of-function and pharmacological inhibition (initially focusing on EP4) using tissue culture models of intestinal tumorigenesis
  2. investigate whether small molecule EP receptor antagonism can be used as an adjunct to existing cancer therapies.
  3. validate in vivo novel PGE2 signalling mechanisms using patient material from our ASPIRE trial to inform future clinical use of EP receptor agonists/antagonists.

Methods

Human cell culture models (including 3D organoids) will be used to model PGE2-mediated cancer phenotypes. Assays will be carried out in both normoxia and hypoxia (1-5% oxygen) to mimic the tumour microenvironment in vitro. Drug treatments will be followed by assays for cell survival/proliferation, stem cell/differentiation, autophagy and metabolism (Seahorse XF). Genetic loss-of-function models using CRISPR-Cas9 (and RNAi) will be generated to complement and validate pharmacological approaches. RNA-seq and bioinformatic analysis (including EdgeR/DESeq2 statistical analyses and GSEA) will be used to define gene signatures and markers of PGE2 signalling. Clinical samples available through the ASPIRE trial will be used for in vivo validation using tumour tissue microarrays (TMAs). Training will be provided for all advanced techniques in modern facilities available at UWE Bristol and the University of Bristol. This studentship will also include opportunities to visit Sosei Heptares to gain exposure to industrial drug discovery and development thinking.

Impact

This project will reveal how novel small molecules targeting PGE2 receptors could be used for the treatment of colorectal cancer. Given the increasing incidence of colorectal cancer in younger individuals (<50), this project has exciting possibilities to further understand the drivers of early onset cancer and to improve the treatment of colorectal cancer in this age group.

For an informal discussion about the studentship, please contact Dr Alex Greenhough (Alexander.Greenhough@uwe.ac.uk) to arrange a Teams/Zoom call.

Funding

The studentship is available from October/November 2021 for a period of three years, subject to satisfactory progress and includes a tax exempt stipend, which is currently £15,609 per annum. All bench fees/consumables are also provided. 

In addition, full-time tuition fees will be covered for up to three years (Home/EU rates only). Overseas applicants will be required to cover the difference between Home/EU and the overseas tuition fee rates in each year of study.

Eligibility

Applicants must have a BSc (2:1 or above) or equivalent degree in a biological or biomedical sciences discipline. Experience in cell biology techniques is desirable but not essential as training will be provided. This studentship is eligible for UK/EU applicants only.

A recognised English language qualification is required.

How to apply

Please submit your application online. When prompted, use the reference number 2021-OCT-HAS06.

Supporting documentation: you will need to upload your research proposal, all your degree certificates and transcripts and your proof of English language proficiency as attachments to your application so please have these available when you complete the application form.

References: you will need to provide details of two referees as part of your application. At least one referee must be an academic referee from the institution that conferred your highest degree. Your referee will be asked for a reference at the time you submit your application, so please ensure that your nominated referees are willing and able to provide references within 14 days of your application being submitted. 

Closing date

The closing date for applications is Sunday 8 August 2021.

Further information

Interviews will take place on TBC. If you have not heard from us by 1 September 2021, we thank you for your application but on this occasion you have not been successful.