Harnessing radiation biology to increase cancer cure rates

Radiotherapy remains a central pillar of cancer care, contributing to 50% of all cures and improving quality-of-life in many with incurable disease.

The reasons why radiotherapy does not always cure are poorly understood but key horizons for overcoming treatment failure include understanding cancer biology, modifying physical parameters governing radiation dose delivery and designing, delivering and learning from optimised clinical trials.

The Institute of Cancer Research and Royal Marsden RadNet Centre of Excellence (ICR/RMH RadNet-CoE) comprises a cohesive, collaborative and effective team, pivotal in delivering our mission of curing more patients with fewer side-effects (e.g. HeartSpare, DELINEATE, DARS, PACE trials).

We are at the forefront of radiation-related research, capitalising on interfaces between world-leading laboratory scientists in DNA repair, cell death, immune response and cancer evolution, and clinicians, radiographers, physicists and research methodologists who design and deliver clinical trials that improve cancer care globally.

ICR/RMH RadNet-CoE-funded team members have leveraged an additional £8 for every £1 granted to RadNet-CoE, expanding our research and the reach of our programme.

Importantly, scientists without an antecedent background in radiation-related research have enriched our team, adding breadth and depth of expertise to our efforts.

In our renewed RadNet-CoE, we will build on these foundations and deliver a bold programme of transformational radiotherapy-focused research.

At the cancer cell level (Theme 1), we will investigate how to block cancer’s radiation-induced DNA damage repair mechanisms, to maximise the cytotoxic power of radiotherapy and augment its ability to trigger sensor mechanisms that boost anti-cancer immune responses.

We will extend existing research on rewiring immunologically-silent apoptosis into immune-triggering cell death, increasing cure rates.

We will study how intratumoural oxygen levels (redox state) can affect cell death mechanisms and immune-mediated cytotoxicity.

Also, recognising that cancers are not static targets but evolve in response to radiotherapy, we will conduct preclinical and translational research to understand this evolutionary process and expose vulnerabilities of cancer cells to novel therapies.

In the tumour microenvironment (TME), we will focus on strategies that improve sensing and response to cues from dying cancer cells (Theme 2).

In particular, we will evaluate modulating the TME in the context of radiotherapy-drug combinations (DNA repair inhibition, pattern-recognition receptor agonists and drivers of immunogenic cell death).

We will invest in infrastructure for profiling treatment-related changes within the TME, leveraging significant infrastructural funding from the ICR (>£1M) and CRIS Foundation (£0.75M).

We will expand existing activity in clinical sample acquisition, processing and analysis using state-of-the-art platforms to validate preclinical findings and generate new hypotheses.

Building on ICR/RM’s track record in developing and evaluating new radiotherapy technologies and schedules, we will assess two new approaches in Theme 3: FLASH and spatially-modulated radiotherapy.

We have the world’s first FLASH-enabled small animal radiotherapy-research platform (SARRP) that delivers ultra-high dose rates up to 180 Gy/s to conventional, broad-beam or spatially-modulated distributions.

Thus, we will make unique contributions to understanding and implementing next-generation transformative radiotherapy technologies.

Moreover, we have access to a nanoparticulate radioenhancer [NBTXR3] that we will profile alongside FLASH and spatially-modulated techniques.

For Themes 1-3, Tier 1 funding will allow us to initiate the activities listed above, whereas Tier 2 funding will power expansion by funding training posts (PhD and post-doctoral training fellows (PDTF)), thus increasing the depth, reach and impact of our work. Our focus is on maximised impact for patients with cancer.

Through practice-changing radiotherapy trials, we have set global gold-standards in the last three decades, especially in breast, urological and head and neck cancers, trials for which we hold biobanks of sample collections.

We have a large suite of ongoing and planned clinical trials where we will add sample collection to full clinical annotation within Theme 4.

We will exploit this unparalleled repository to perform “reverse translation”, integrating patient data with molecular analysis, linking fundamental science to patient impact.

To accelerate achieving these aims, our request for Tier 2 funding resources the training of future radiation researchers through dedicated multi-disciplinary research time, creating new connections between RadNet-CoE Themes.

We will implement new training programmes to recruit and empower allied healthcare professionals (AHP) to realise their potential in contributing to radiotherapy research.

By supporting the UK Early Career Researchers in Cancer (ERCC) network, we will contribute to a national programme supporting nascent radiation researchers.