Professor Ester Hammond Awarded Brain Research UK Funding to Tackle Paediatric High-Grade Glioma

Paediatric high-grade gliomas (pHGG) are rare, aggressive, and highly invasive brain tumours, accounting for over 40% of all childhood brain tumour death. Standard of care treatment relies primarily on radiotherapy, but prognosis remains poor, with a median survival of only nine to 15 months. There is an urgent need for new treatment strategies that improve survival without harming the developing brain.

A new Brain Research UK-funded project led by Professor Ester Hammond aims to enhance the effectiveness of radiotherapy by exploiting a biological vulnerability in pHGG cells: their high levels of reactive oxygen species (ROS).

ROS are essential for normal cell function, but their levels must be tightly regulated. Excessive ROS can cause irreparable damage to cells and trigger cell death. Cancer cells, including pHGG, undergo metabolic reprogramming to meet their increased energy demands, resulting in chronically elevated ROS levels. This places them closer to a critical threshold for survival, creating a therapeutic opportunity to push ROS levels beyond what the tumour cells can tolerate.

Previous experimental treatments designed to boost ROS levels have done so in healthy cells as well as cancer cells, leading to unacceptable toxicity. Prof. Hammond’s team will investigate a unique experimental agent known as Ag5, a cluster of covalently bonded silver atoms, designed to selectively increase ROS levels in cancer cells, without impacting healthy cells.

In environments where ROS levels are already high, such as in tumour tissue, Ag5 inhibits key antioxidant systems, limiting cellular antioxidant capacity. This inhibition fuels a positive feedback loop that further increases ROS, ultimately triggering cancer cell death. This mechanism may be particularly effective in pHGG, which is thought to be especially sensitive to ROS-induced cell death due to characteristic molecular alterations.

Importantly, because healthy brain tissue maintains lower baseline ROS levels, Ag5 will selectively target tumour cells while sparing normal cells.

There is also a strong scientific rationale for combining Ag5 with radiotherapy. Radiation treatment works in part by generating ROS to damage tumour DNA. By further amplifying ROS levels, Ag5 could enhance the tumour-killing effects of radiation.

Early work in the Hammond lab has shown that Ag5 alone reduces viability in pHGG cell lines and increases sensitivity to radiation when used in combination. This Ag5-mediated loss of viability was also observed under hypoxic conditions that mimic the tumour microenvironment. 

Building on these data, the new project will systematically test the combination of Ag5 and radiation across a panel of cell lines representing multiple pHGG subtypes, as well as normal astrocytes. Cell viability studies will assess how ROS levels impact survival and whether common molecular features of pHGG influence sensitivity to the drug.

To support rapid clinical translation, the team will also evaluate alternative dosing strategies, including single and fractionated regimens and varying schedules of Ag5 administration relative to radiation delivery. The most effective schedule will then be advanced for in vivo testing.

Professor Hammond said:

“We are extremely grateful to Brain Research UK for enabling us to pursue this work. By selectively targeting the oxidative stress vulnerability of pHGG cells, we hope to develop a strategy that works in concert with existing therapies and moves us closer to more effective treatments for children with this devastating disease.”

Through the support of Brain Research UK, this project aims to generate robust evidence for a novel radiosensitisation strategy, laying the groundwork for future clinical development in pHGG.