Project: Overcoming chemoresistance in breast and colon cancer

Challenge Space

Health - Resistance

Prinicipal Investigator(s) and team names

Dr Darren Fayne, Molecular Design Group, with Profs Mary Meegan, Niamh O’Boyle and Daniela Zisterer, TCD

Collaborating Institutions

Funding support

Project start date

January 2017

End date

Current

Problem

Chemotherapy frequently works at first and then stops. 

Cancer cells have several ways of arranging this: pumping the drug back out before it can act, or chemically modifying it so that it is disposed of as waste. Once either is established, an entire class of drugs can lose its effect at the same time, and patients whose disease returns are often returning to a shorter list of options.

Background

 In a long-running collaboration with medicinal chemists and cell biologists at Trinity College Dublin, the group has designed and evaluated successive families of compounds that disrupt the internal scaffolding cancer cells need in order to divide. 

Several have shown activity in cell lines selected for resistance to existing agents, including multidrug-resistant leukaemia samples taken from patients. One series was designed specifically so that it could not undergo the chemical modification by which resistant colon cancer cells inactivate the parent drug.

Solution

The group's role is the design side: modelling how each candidate sits against its target, explaining why particular structural changes improve or destroy activity, and using that to direct the next round of synthesis rather than making compounds at random. 

The partnership continues, with recent work published in 2025 on compounds active in both breast cancer and chemoresistant colon cancer cells. 

The wider point holds across the group's work: resistance is easier to design around when it is understood as a change in shape and chemistry at a specific site, which is something computation can model directly.