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Targeting CES1 to improve the treatment of aggressive colorectal carcinoma

  • School: School of Science and Technology
  • Study mode(s): Full-time / Part-time
  • Starting: 2023
  • Funding: UK student / EU student (non-UK) / International student (non-EU) / Fully-funded

Overview

NTU's Fully-funded PhD Studentship Scheme 2023

Project ID: S&T6

Colorectal carcinoma (CRC) is the second deadliest cancer worldwide with a 5-year Overall-Survival rate of less than 10%. CRC has been classified in four main consensus  molecular subtypes (CMS1-4). Except for immune  checkpoint immunotherapy, indicated in microsatellite-unstable/hypermutated CRC (CMS1), current treatments consist of front-line combination chemotherapies. Thus, new treatments are needed to improve the management of patients with CMS2-CMS4/microsatellite-stable/non-hypermutated metastatic CRC. Recently, we identified   carboxylesterase1 (CES1) as an essential NF-κB-regulated triacylglycerol lipase linking lipid catabolism and metabolic adaptation to energy stress in aggressive CRC. Interestingly, CES1 expression is upregulated in CMS4 and CMS2  tumours and correlates with worse clinical outcomes. Furthermore, treatments with CES1 inhibitors effectively killed human CRC cells upon glucose limitation. Collectively, these results identify CES1 as a druggable therapeutic target in CRC and support the therapeutic potential of blocking CES1to counter colorectal carcinogenesis.

The current proposal will aim to:

1. Investigate CES1 role in non-cancerous cells of the tumour microenvironment (TME).

Although data underscore the importance of the CES1-dependent metabolic mechanism in CRC cells, they do not exclude additional roles of CES1 in the symbiosis between TME-based cells and cancer cells that fuel tumour progression. The proposal aims to clarify these potential   added roles of CES1 in TME-associated populations, and to investigate how targeting CES1 could affect their function and CRC evolution. In particular, by  using single-cell-RNA-sequencing data from CRC patients and integrating gene expression and functional pathways, cell populations that express CES1 will be characterised in terms of biological features; a cell-cell interaction network will be created to define how these key cell populations are involved in regulating tumorigenesis and cancer immune evasion; the correlation between these identified CES1-expressing subsets with CMS status, genomic alterations, and other clinical features will be evaluated.

2. Develop CES1 inhibitors with improved bioavailability.

The  short half life and poor drug-like properties of the two available CES1 inhibitors highlight the need for developing CES1 inhibitors with improved bioavailability. As part of this targeted approach, a ligand-based virtual screening of a curated library of 800,000 molecules with chemical diversity using  the inhibitors as template was conducted. The proposal aims to identify a panel of structurally diverse CES1 inhibitors exhibiting: high activity and specificity in invitro CES1 enzymatic assays; efficient CES1 inhibition in 2D/3D cell lines cultures; favourable drug-like properties.

Supervisory Team:

Supervisor: Dr Daniel D’Andrea (Lecturer in Bioinformatics)

Co-Supervisors:

Dr Silvia Ottaviani (Senior Lecturer in Molecular Cell Biology)

Dr Ben Dickins  (Senior Lecturer in molecular biology, biochemistry and evolution)

Entry qualifications

For the eligibility criteria, visit our studentship application page.

How to apply

To make an application, please visit our studentship application page.

Fees and funding

This is part of NTU's 2023 fully-funded PhD Studentship Scheme.

Guidance and support

Application guidance can be found on our studentship application page.

Still need help?

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