Understanding the role of IKKα in the tumour microenvironment and establishing it as a novel therapeutic target in colorectal cancer

Prof Joanne Edwards, Dr Lesley Stark, Dr Nigel Jamieson

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Labs:
Edwards Group
Stark Group
Jamieson Group
Duration: 4 years from September 2022
Closing Date: 27th May 2022

About us

Applications are invited from outstanding candidates to join a Cancer Research UK funded PhD programme at the Institute of Cancer Sciences, University of Glasgow. These are funded by the Cancer Research UK Scotland Centre, a joint initiative between Edinburgh and Glasgow which brings together cancer scientists and clinicians from across the Universities of Edinburgh and Glasgow, delivering outstanding cancer research and improved patient care. The Cancer Research UK PhD programme is integrated into the research activities of the Centre with over 80 principal investigators contributing to this cross-disciplinary programme spanning from fundamental science to translational research. Research projects benefit from state-of-the art facilities for genomics, mass spectrometry, advanced microscopy, single cell technologies, and from advanced computational and informatics capabilities.

Project description

Colorectal cancer (CRC) remains the 2nd most common cancer and 3rd most common cause of cancer-related death globally. Despite advancements in treatment of disease through recent adoption of immunotherapies, novel therapies are required to improve patient outcomes. IKKa represents a promising therapeutic target and is involved in non-canonical NF-κB signalling. This pathway is activated by either RANK/RANKL, CD40/CD40L, LTbR/ LTb or BAFF/BAFFR ligand receptor interaction, leading to subsequent activation of NIK and IKKa. This results in phosphorylation and ubiquitination of the p100/RelB complex, which translocates to the nucleus and acts as a master regulator of genes associated with the hallmarks of cancer. We have demonstrated that high expression of IKKa is associated with reduced prognosis in prostate, breast, and right-sided colon cancer (1-3). Evidence from other groups utilising CRC cell lines suggests that IKKa may also be involved in the canonical NF-κB pathway. This project aims to further our understanding of IKKa role in NF-κB signal transduction within the tumour microenvironment (TME), investigate downstream pathways of IKKa activation and explore the therapeutic potential of combining IKKa inhibitors with chemotherapy for colon cancer and radiotherapy for rectal cancer through in vitro studies.

To study IKKa in the TME we will use retrospective discovery, validation and clinical trial CRC cohorts, which will be stained via multiplex immunohistochemistry (mIF) for total IKKα expression, phosphorylated IKKa at serine 176 and tyrosine 23 (markers of IKKa activation), aSMA, pCK, CD3, CD68 and CD66b. Data will be analysed digitally using Visiopharm®. Outputs will be assessed for association with clinical characteristics and outcomes to identify which markers (eg total IKKa or phosphorylated IKKa at serine 176 and tyrosine) and in which cells (specific immune cells e.g. CD3 positive or CD68 positive) have the highest prognostic power. Nanostring GeoMx spatial transcriptomics will be performed on the immune, fibroblast and tumour cell populations that express total or phosphorylated IKKa to identify up or down stream pathways of interest. Pathways of interest will be explored/validated in both cohorts from mIF experiments to assess expression in patient tissue. Cell pellets and patient tissue will be stained via chromogenic IHC to validate these data at the protein level. Drug screening with first-in-class IKKa inhibitors with fluorouracil (5FU) or 0-6Gys radiation will be performed on 2D monocultures of colon (HT29, HCT116) and rectal cells (SW837, CaCo2) respectively. Responses will be measured using WST-1 cell viability assays, clonogenics and functional assays identified as important through RNASeq experiments. Drug screening will also be performed with cell lines grown as cocultures with fibroblasts, macrophages or lymphocytes depending on mIF results, and in a small cohort (n=10) of patient-derived organoids.

This project will further our understanding of the role of IKKa in the TME and which subpopulation of CRC patients may benefit from therapeutic inhibition of IKKa in CRC. Finally, the use of IKKa inhibitors in combination with standard of care chemo/chemoradiotherapy will be investigated in recapitulative preclinical models as a step towards moving this novel targeted therapy towards clinical trials for patients with CRC.

Application procedure

Up to 3 studentships are available to start in September 2022 for outstanding applicants with a stipend of £19,000 p/a. These are funded by the CRUK Scotland Centre, a joint initiative between Edinburgh and Glasgow. Successful students will be registered for their degree in either Glasgow or Edinburgh, depending on the project they apply for.

We are looking for students with a very good degree in a Life Sciences subject and an aptitude for experimental work, who are also highly committed to pursuing a PhD and a career in cancer research. You should hold at least an upper second-class degree in a relevant subject and comply with English language requirements.

All applications will be administered centrally via the University of Edinburgh, please apply on the link below - this includes Glasgow-based projects with Glasgow-based supervisors: https://www.star.euclid.ed.ac.uk/public/urd/sits.urd/run/siw_ipp_lgn.login?process=siw_ipp_app&code1=PRPHDCECRC1F&code2=0020

Closing date: 27 May 2022

Interviews are expected to be held week beginning 27 June.

Applications are open to all individuals irrespective of nationality or country of residence.

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