Ben O’Leary

Presentation
Radiotherapy has been used to effectively cure and palliate cancer for over a hundred years, yet there remains significant uncertainty around the mechanisms that underpin sensitivity or resistance to treatment, in the case of curative-intent treatment the difference between life and death.

In head and neck squamous cell carcinomas (HNSCC) specifically, the human papillomavirus (HPV) positive or negative subtypes effectively identify two groups of vastly differing radiotherapy sensitivity, though the reasons for this difference remain unclear, and it has not been possible to reliably identify factors that predispose to resistance that could be used in the clinic. The clinical unmet need is substantial – many HNSCC can be treated with surgery-led or radiotherapy-led treatment, and where there is clinical equipoise, an understanding of mechanisms of radiotherapy resistance is necessary both to rationally select treatment, but also to identify novel treatment approaches to overcome radiotherapy resistance. For HPV+ HNSCC, an important question has become how to safely de-escalate radiotherapy. Radiotherapy remains the key non-surgical treatment, with only marginal benefits achieved with the addition of systemic therapies to date, historically with cisplatin and recently with PD-1 checkpoint inhibitors.

Recent work demonstrating high levels of disease control with dramatic dose de-escalation to 30Gy based on on-treatment FMISO PET to identify hypoxia has shown that sub populations of patients with HPV+ HNSCC can potentially be treated with much lower than conventional doses, but larger trials of this approach are awaited. At a more mechanistic level, the DNA damage response is a logical target for augmenting radiotherapy efficacy, with promising early phase data for agents such as ATR inhibitors resulting in currently recruiting phase III randomised controlled trials.

Following the model successfully implemented in other cancers for administration of adjuvant chemotherapy, predictive scores based on gene expression for sensitivity to radiotherapy have been developed but are not widely used, in part because of concerns about how broad their applicability might be and how representative they are of underlying biology. Genomic studies examining copy number show changes through radiotherapy in HNSCC, with markedly different profiles in recurrence, and copy number signatures demonstrating association with outcomes. These signatures in many cases reflect mechanistic aspects of genome instability and could provide opportunities for novel therapeutic combinations with radiotherapy. Recent data focused on targeted DNA sequencing from the NRG/RTOG 9512 trial of dose escalation in early glottic cancer, identified that patients with mutations in NFE2L2, KEAP1, CUL3, genes involved in the cellular antioxidant response, had significantly higher rates of local control and worse disease-free survival. These results show promise for future work aiming to build biologically informed radiotherapy sensitivity predictors for HNSCC, and for unpicking the underlying mechanisms to help identify new treatment approaches.

Bio
Ben leads the Evolution & Translational Genomics Group at The Institute of Cancer Research and is an Honorary Consultant in Clinical Oncology at The Royal Marsden Hospital. Ben’s research is focused on understanding the evolution of resistance to cancer therapies in head and neck cancers, including the use of liquid biopsies. He leads several translational studies and clinical trials at The Institute of Cancer Research and The Royal Marsden.

Ben initially completed a degree in Aerospace Engineering at the University of Cambridge before training in medicine at King’s College London. After junior medical training in London he was awarded an NIHR Academic Clinical Fellowship in Clinical Oncology in 2012 at The Royal Marsden Hospital, The Royal Sussex Hospital, and The Institute of Cancer Research.

Ben then undertook a Medical Research Council Clinical Research Training Fellowship in Professor Nick Turner’s Molecular Oncology lab at The Institute of Cancer Research in 2015, working on circulating tumour DNA and the evolution of resistance to CDK4/6 inhibitors. Subsequently, he was appointed as an NIHR Academic Clinical Lecturer in 2019, with a visiting position in Peter Van Loo’s Group at The Crick in London, then MD Anderson Cancer Center in Texas, working on cancer evolution. He was appointed as Clinician Scientist at The Institute for Cancer Research and The Royal Marsden Hospital in 2022. In 2024, Ben received a Wellcome Discovery Research Early Career Fellowship to support his research into the evolution of treatment resistance in head and neck cancer.