Editorial

To develop new targeted treatments, our researchers need to uncover the cellular and molecular changes underpinning different cancers.

Cancer still has many secrets we are working to uncover:

• Cancer cells can change over time as genetic mutations alter their appearance or behaviour. Some changes help the cells survive, and they can pass this advantage on when they divide. This can sometimes lead to treatment resistance, where a therapy stops working. Our researchers are working on exploiting this by altering cancer’s environment to make the cells evolve in a way that renders them more susceptible to treatment.
• Complex interactions between the immune system and cancer can influence the mutations promoting the disease’s growth and spread. Our scientists, including Dr Annie Baker, have developed a technique for analysing how the immune system responds to cancer cells with different mutations as the disease progresses.
• The microbiome – the collection of microbes in and on the body – has links to cancer evolution. After finding that a specific variation of a common bacteria seems to increase the risk of colon cancer, our researchers are working to better understand the role of gut bacteria in cancer initiation and progression.
• Non-cancerous cells close to tumours can affect how a treatment responds. Our scientists are researching the many different proteins that these cells secrete, some of which can increase cancer’s resistance to chemotherapy.

By understanding all these factors, our scientists will have a better idea of how cancer develops, spreads and becomes resistant to treatment, which will help them find new ways to prevent and treat the disease.

Proteins are one of the key molecules in our body, and they are essential for every cell function, including growth, signalling and survival. When they become faulty or overactive, they can drive cancer. Traditionally, cancer therapies have aimed to block the activity of these proteins, but this often proves challenging.

Targeted protein degradation is a cutting-edge approach that kills cancer cells – not by temporarily inhibiting cancer-driving proteins but by removing them entirely. It uses specially designed small molecules such as PROTACs and molecular glue degraders, which cause the cancer target protein to interact with a cellular enzyme called E3 ligase. E3 ligase uses a marker called ubiquitin to flag the protein for degradation by the cell’s natural recycling system.

Unlike inhibitor drugs, which stop a protein from working, degradation-based therapeutics offer the potential to target cancer proteins previously considered undruggable. Effective in lower doses, they reduce the risks of side effects and drug resistance – two major hurdles in cancer therapy.

Dr Agnieszka Konopacka leads drug discovery biology at our Centre for Protein Degradation. Her research team develops models and tools to study molecular glue degraders and PROTACs at a highly detailed level. The team is also working to discover new cancer targets and E3 ligases to help patients with hard-to-treat cancers.

With our strong legacy in drug discovery and focus on developing innovative technologies, we are shaping a future where challenging cancers can be treated effectively and safely.

Historically, we have achieved this using a technique called X-ray crystallography, which involves passing an X-ray beam through a specially prepared sample (protein crystal) and then using the diffraction pattern to reconstruct the molecule’s three-dimensional structure.

However, this approach is not suitable for all biological molecules, particularly those that are larger or more complex. As a result, cryo-electron microscopy (cryo-EM) has become popular. This cutting-edge technique reveals the detailed structure of a biological molecule by rapidly freezing samples to below -150°C before passing a beam of electrons through them to collect images from different angles. A computer can use these to create a three-dimensional model of the molecule.

Our scientists, including Victoria Cushing, recently led the development of an improved cryo-EM process that produces higher-resolution images in a significantly shorter timeframe. The first stage involves rapid screening using a more accessible cryo-EM instrument, during which the researchers assess the resulting images to select the specimens with the highest potential. In the second stage, a high-end microscope – which has a cold field emission gun machine that emits a highly coherent electron beam – is used to provide more detailed images of the selected molecules.

Using this approach, researchers can achieve exceptional images showing individual atoms and their interactions. They can also work faster, so they can determine the structure of multiple protein complexes each day.

This methodological advance has overcome a longstanding technical challenge, increasing both resolution and speed. By providing researchers with such a detailed view of molecules of interest, it has the potential to aid drug discovery on a large scale – across research institutions worldwide and across cancer types.

Once they have discovered a potential cancer target, they face the significant challenge of getting it into a drug discovery programme to progress it to clinical trials. To bridge this gap, we established the Centre for Target Validation (CTV), which sits within the Centre for Cancer Drug Discovery.

The CTV aims to identify candidate targets from across the wide spectrum of our laboratories and carry out in-depth therapeutic target validation to inform the launch of successful drug discovery projects.

The team benefits from the leadership of Dr Joanna Loizou, a specialist in genome stability and DNA repair pathways with a strong background in translational medicine. Dr Loizou, who joined us in November 2024 to take on the role of Deputy Director of the CTV, said:

“Our centre was created to select and validate targets identified by the world-class research at the ICR. Using a fast and streamlined approach, we can take targets through to drug discovery projects, which we have the necessary facilities and expertise to lead onsite.

“Failure rates of drugs in clinical trials are high, and a principal reason of failure is lack of effectiveness. By having a robust target identification and validation dataset and using the right preclinical experiments, we should be able to improve the success rate of new cancer drugs, which we hope will be more effective and better tolerated.”

The CTV will incorporate the newest available techniques into its workstreams and draw on both publicly available data and its own broad target validation datasets to select targets with the most potential.

“We’re looking for targets with clinical rationale,” said Dr Loizou. “For instance, those with molecules that might be sensitive to the inhibition of another protein. If the chemistry is right, we should be able to get all the way to the clinic.”