Mechanistic modelling of multitargeted therapeutics
LEAD SUPERVISOR: Prof Eric O’Neill, Department of Oncology
Co-supervisor: Prof Helen Byrne, Mathematical Institute
Commercial partner: EPICOMBI.ai
Pancreatic cancers remain intractable, resulting in high mortality. Thus, there is an urgent need for innovative ways to tackle this disease. Aberrant epigenetics is a key “Hallmark of cancer" that cancer cells use to drive de-differentiation of normal cells into an embryonic squamous-like state which favours uncontrolled proliferation. We recently identified the epigenetic mechanism defining these phenotypic changes and found that a combination of biologically-targeted agents (Metformin and Vitamin C) could restore epigenetic control and revert squamous pancreatic cancer cells to a more regulated differentiated state . Although we observe a shift towards normal cell epigenetics, this drug combination is not fully optimised to drive the phenotypic shift. Therefore, we aim to use an innovative data-driven artificial intelligence (AI) approach developed by Epicombi.ai, based on existing algorithms, to delineate novel molecules that can demonstrate improved and robust re-normalisation of epigenetic status and pancreatic differentiation, in order to offer new treatments for this hitherto intractable cancer.
Our aim is to develop mechanistic mathematical models for AI-derived molecules targeting pancreatic cancer.
The proposed project will explore the mechanism of action of molecules predicted by a AI/Machine Learning platform (Epicombi.ai) to modify cellular phenotype. This project will centre on the development of mechanistic models [3,4] to better understand how these novel agents achieve phenotypic changes through the perturbation of relevant cellular signalling networks. These molecules are likely to have multiple cellular targets, perturbing a number of signalling pathways, which may all combine to achieving phenotypic normalisation of the cell. Thus, mechanistic modelling is required to understand how such a ‘multi-intervention’ molecule functions to alter cell signalling networks. The models will then be employed to further refine the platform discovery and optimisation engine, and provide a mechanistic underpinning of Epicombi.ai data-driven drug-discovery platform to identify optimised drugs for this therapeutic indication.
 Eyres et al. (2021) Gastroenterology. 2021:S0016-5085(21)00682-X.
 Pham et al. (2021). Nat. Mach. Intell. 3, 247–257
 Kay et al (2017). PLoS Comp Biol. 2017; 13(2): e1005400.
 MacLean et al. (2015) PNAS. 2015; 112(9): 2652-2657.
Apply using course: DPhil in Oncology