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Radiation Research Centre of Excellence (RadNet)

Radnet-ICR-RMH_RGB_2023

The Radiation Research Centre of Excellence (RadNet) at the ICR and The Royal Marsden brings together world-leading experts in radiotherapy, immunotherapy, cancer biology and targeted drug treatment to collaborate on new forms of combination treatment.

Radiotherapy machine at The Royal Marsden Hospital (photo: Jan Chlebik/the ICR)

The Centre’s central goal is to link discovery, translational and clinical research with direct line of sight to patient benefit. Led by Professors Kevin Harrington and Nicholas van As, the Centre seeks to improve outcomes for cancer patients by understanding and modulating fundamental biological processes that occur in irradiated tumour and normal cells. In addition to biological effects, researchers will challenge dogma relating to physical concepts of radiotherapy delivery, particularly regarding spatial, dose-rate and dose-fractionation aspects of therapy. 

The Centre is based on five preclinical and clinical research themes:

  1. Molecular responses to radiation-induced DNA damage
  2. Innate/adaptive immune responses
  3. Clinical translation
  4. Mechanisms of cell death
  5. Radiation delivery platforms

 

Research themes

1. Molecular responses to radiation-induced DNA damage

Led by Professor Jon Pines

RT-induced cell death mainly occurs through DNA damage in the form of double-strand breaks (DSBs). Differences between tumour and normal cells in their DSB repair responses are responsible for the clinical success of RT but, presently, we lack molecular insights to predict individual patient responses. Radiation responses must be considered both at the level of cancer cells and in the context of a complex tumour environment. In this theme, we draw on our expertise in genome stability to propose new research investigating cellular responses to RT, focussing on the effects of radiation on mitotic control/aneuploidy, genomic instability, double-strand break repair and cGAS/STING pathway.

2. Innate/adaptive immune responses

Led by Professor Kevin Harrington

This theme will build on our expertise in biological therapies to deliver new research to study RT-induced innate and adaptive immune responses focussing on three approaches: (i) the use of oncolytic viruses as modulators of RT-induced anti-tumour immunity; (ii) the use of non-viral activators of innate immune sensors; (iii) enhancing RT—induced immune responses with small-molecule modulators of molecular responses to radiation-induced DNA damage.

3. Clinical Translation

Led by Professor Nicholas van As

Our Centre supports dedicated research time for radiation oncologists to enable us to drive both forward and reverse translation from our other themes. We will conduct phase I studies of RT with line of sight to future trials powered for identified biological endpoints, including the delivery of novel sub-studies in patients taking part in national and international Royal Marsden-led RT trials to augment our understanding of biological markers of clinical response.

4. Mechanisms of Cell Death

Led by Professor Pascal Meier

Cells can die in many ways: some forms of death are immunogenic, others are immunologically silent or even tolerogenic. Immunogenic cell death (ICD) is not yet fully defined, but specific types of death (e.g. necroptosis) maximally drive antigen cross-priming of CD8+ T cells. This is because such programmes trigger cell death as well as NF-κB- and interferon-dependent production and release of ‘danger signals’ from dying cells that attract and stimulate immune cells. A central aim of this theme is to manipulate cell death and innate immune mechanisms so that RT maximally triggers cytotoxicity and the coordinated production of danger signals.

5. Radiation Delivery Platforms

Led by Professor Uwe Oelfke

Conventional radiotherapy (RT) dose-fractionation schedules are given at dose-rates around 0.03 Gy/s. Alternative approaches such as ultrahigh dose-rate radiotherapy (UHDR RT) deliver treatment at >40 Gy/s. The biological effects of UHDR RT remain uncharacterised but preclinical animal studies suggest impressive anti-tumour effects with reduced acute/late toxic effects. Microbeam radiotherapy (MBRT) is a radically new approach in which a homogeneous RT field is divided into planar high and low-dose regions on a micrometre scale. Pre-clinical evidence shows that MBRT effectively destroys tumours with limited damage to surrounding healthy tissues. The underlying radiobiological mechanisms of these effects are not understood at present. Our Centre aims to study and define the mechanistic bases for the biological effects of UHDR RT and MBRT with respect to molecular responses to DNA damage, tumour cell death and effects on innate and adaptive immune responses.

Latest News

First-in-world trial completes

The HERMES trial, led by Dr Alison Tree and Professor Emma Hall, is the first randomised trial in the world to test just two treatments of radiotherapy on the MR linac. The trial has embedded translational work to examine the immune consequences of very high dose per fraction. The interim analysis, published last year shows that the treatment, designed to cure prostate cancer, has lower levels of side effects than expected. The trial has now completed and full clinical analysis is expected to be presented in 2024.

HERMES trial

The MR linac featured on the award-winning RadChat podcast

The MR linac team, including doctors, radiographers and one of our patient advocates, have been interviewed as part of a 6-part podcast series on our MR linac research, as part of the MR linac consortium.
 
Click here to hear from one of the patients partnering with us in research.

Student success at national bladder cancer meeting

Amy Burley, a PhD student in the Stromal Radiobiology group led by Dr. Anna Wilkins, was recently awarded the prize for the best oral presentation at the 6th Bladder Cancer Translational Research Meeting.

Amy’s abstract was selected as one of the top three submissions and she was invited to give a talk summarising her work looking at strategies to predict radiotherapy recurrence in bladder cancer. 

Looking at the genetic profiles of patients treated with radiotherapy, Amy has found that an enrichment for signatures linked to fibrotic cells in the tumour microenvironment was associated with significantly worse outcomes. 

The audience were impressed by Amy’s observations and were encouraged by her plans to correlate these findings with multiplexed imaging data (see image below).

Amy’s analysis helps us to understand the mechanisms that drive radiotherapy resistance in bladder cancer and may identify new opportunities to improve responses to this treatment.

 

RadNet prize winner

A multiplexed image of the tumour microenvironment in a bladder cancer sample. Tumour cells are shown in white and diverse populations of fibrotic cells are shown in orange, red, yellow and green.

Ceralasertib could unlock benefits of immunotherapy for more patients

Ceralasertib showed promise for patients no longer responding to current cancer treatments in an early clinical trial. Given on its own, the drug stabilised the growth of tumours in more than half of patients who received it, with one patient seeing benefits for more than five years. Click here for more information.

Radiation immunity projects funded

The ICR’s Genome Stability and Innate Immunity Group, headed by Dr Christian Zierhut, studies how the genotoxic stress that is associated with cancer can be exploited to promote immune responses. The group has a special interest in radiotherapy, and most of the group’s work is closely associated with the ICR/RM Radiation Research Centre of Excellence. Recently, two new projects were funded for work carried out by the group, both of which build on, and expand, previous insight generated in association with the Centre of Excellence. The first of these is funded by a project grant from Breast Cancer Now. It will make use of novel single-cell analysis tools that the group previously developed to investigate how the DNA repair-defective mutations that can be associated with breast cancer impact on cellular immune responses. Initially, this research will focus on a class of anti-cancer drugs that are known as PARP inhibitors, and subsequently, the group will also apply their efforts on investigating radiotherapy-related responses.

The second project is funded by the Japan Agency for Medical Research and Development (AMED), and allows Dr Tomoya Kujirai from the University of Tokyo to carry out a sabbatical in Dr Zierhut’s group at the ICR. In this project, the researchers will build on previous collaborative work, and generate a detailed biochemical picture of how DNA-damage induced immune responses are controlled. Altogether, the conclusions drawn from these projects are expected to lead to new approaches for stratifying patients for radiotherapy, and to new co-treatments that can make radiotherapy more effective.

RadNet image signalling

Credit: Vicente Lebrec/ICR. A cell undergoing radiation-induced immune responses.

Review article on immune regulation of genome instability published

In a newly published review article, entitled ‘Potential cGAS-STING pathway functions in DNA damage responses, DNA replication and DNA repair’, Dr Zierhut, who leads the Genome Stability and Innate Immunity Group at the ICR, summarises the available evidence on innate immune regulation of genome stability, and suggests solutions to potentially conflicting data. The full paper is available here.