Translational Radiobiology

Translational Radiobiology in Manchester

The biggest achievements relate to carrying out large studies measuring biology in patients undergoing radiotherapy. Professor Catharine West showed radioresistant tumours are likely to recur and that patients with radiosensitive blood cells are likely to suffer with long-term toxicities. Professor Ananya Choudhury showed that MRE11 expression in bladder cancers identifies patients who benefit from radiotherapy rather than surgery.

One exemplar is the RAPPER study, which involved the collection blood samples from >10,000 patients recruited into radiotherapy trials across the UK. RAPPER is the world’s largest radiogenomics cohort and underpinned the establishment of an international Radiogenomics Consortium that Manchester co-leads.

Collaborative radiogenomics research is identifying new genetic variants associated with an increased risk of radiotherapy toxicity. Manchester also leads the European Union funded REQUITE project, which brings together 15 prominent institutions across Europe and the US. REQUITE collected samples and data from >4,440 patients to produce a centralised resource for the radiotherapy community to develop and test models that predict risk of toxicity.

Other big achievements relate to work generating and validating gene signatures that assess tumour hypoxia. While other groups attempt to derive biomarkers for radiotherapy patients, few focus on the need to validate and progress biomarkers for clinical application. Work by the group led to the UK NIMRAD trial, which randomised older patients with head and neck cancer to radiotherapy alone or with hypoxia-modifying treatment. The trial was designed to test whether our gene signature can be used in routine clinical practice to improve the number of cancer patients cured.

Case study: REQUITE

The ability to derive and validate models that predict a cancer patient’s risk of toxicity following radiotherapy is hampered by the lack of databases for their validation. A limitation to research in the area is that information on long-term toxicity is not collected routinely in most cancer centres. When researchers do collect toxicity data different methods are used. Also, there are multiple factors that affect the risk of toxicity, e.g., whether a patient smokes, and the information is not always available. These limitations make is very difficult to validate models, i.e., test them in multiple cohorts to ensure they are robust enough for clinical application.

The REQUITE study, led by Prof. Catharine West and funded by the European Commission, was established to address previous limitations. REQUITE completed a prospective, longitudinal, multi-national study that recruited >4,440 patients who had radiotherapy for breast, prostate or lung cancer. We compiled a large centralised, standardised dataset and biorepository for validating models and biomarkers that predict a cancer patient’s risk of radiotherapy toxicity.

The study collected high quality standardised data including information on treatment, underlying health conditions, toxicity and patient reported outcomes along with genotyping data. Patients are being followed for up to 5 years. Discovery and access to the anonymised quality-controlled data (>40,000 data points) is via an interface developed at the University of Leicester. A linked biorepository in Manchester stores germline DNA and PAXgene bloods (for RNA). The resource is the first in the world to produce a centralised resource for validating models that predict a patient’s risk of toxicity following radiotherapy.

Further resources on the REQUIE Study can be found through the following links:

• The REQUITE study: An animation overview (2 mins 22 seconds)
• The REQUITE study: Information for Healthcare Professionals video (3 mins 19 seconds)
• The REQUITE study: Information for Patients video (3 mins 28 seconds)

Future Aspirations in Translational Radiobiology

The team hopes to run new trials that test whether hypoxia signatures can be used to personalise treatments and increase the number of cancer patients cured. The group is testing state-of-the-art approaches for generating signature scores that can integrate into patient pathways. The group are also continuing to work with industry to test new approaches for targeting tumour hypoxia and explore the use of imaging enabled by the latest technology for delivering radiotherapy.

Research by the Translational Radiobiology group aims to be world-leading in showing how biomarkers can be used to personalise radiotherapy schedules. The Translational Radiobiology group recently set up a spin-out company ManTRa DX to deliver signatures in clinical trials and as companion diagnostics to personalise cancer treatments.