Blocking brain damage may slow growth of brain cancer

(Press-News.org) Blocking brain damage triggered by a glioblastoma, an aggressive brain cancer, may slow the growth of the cancer and allow the brain to keep working better for longer, according to a new study led by UCL (University College London) researchers.

The study, published in Nature and funded by the Brain Tumour Charity and Cancer Research UK, looked at glioblastomas in mice. It found that early-stage tumours damaged parts of nerve cells called axons, and that the brain’s natural response to this injury – breaking down and clearing away these damaged axons – accelerated the tumour’s growth.

Mice in whom this natural response was turned off developed less aggressive tumours, lived for longer and maintained normal brain function that persisted to nearly the end of their lives. In contrast, mice who responded to nerve damage as normal developed more aggressive tumours and progressive disability, the researchers found.

Drugs that block this response, by targeting SARM1, the protein that destroys damaged axons, are already being developed for early phase trials in neurodegenerative conditions in which axons are also damaged, such as traumatic brain injury (TBI) and motor neuron disease (MND).

Senior author Professor Simona Parrinello, of the UCL Cancer Institute, said: “Our study reveals a new way that we could potentially delay or even prevent glioblastomas from progressing to a more advanced state.

“This is especially important as current therapies do not work well for glioblastoma, which is extremely difficult to treat, in part because it is typically diagnosed when it is already very advanced.

“These tumours are also linked to debilitating neurological symptoms. Blocking the brain damage triggered by tumour growth could be beneficial in two ways - by slowing the progression of the cancer and by reducing disability.

“The next step is to see if SARM1 inhibitors already being trialled for other neurodegenerative diseases could also be used to treat this aggressive form of brain cancer. However, we need to do more work in the lab before these inhibitors can be tried in patients with glioblastoma.”

Glioblastomas are the most common form of brain cancer, with about 3,000 people diagnosed in the UK each year. They grow from normal brain cells that develop pathological mutations. The average survival time after diagnosis is about 12-18 months, even with the current best treatment (a combination of surgery, chemotherapy and radiotherapy).

In the new study, the researchers sought to investigate how the tumours formed and evolved in their earliest stages. These early states of the disease are not well understood as the tumours tend to be discovered only when they are more developed. As it is rare to identify and access samples from patients with early-stage disease, the researchers used mice whose genes had been edited to grow glioblastomas comparable to human tumours to look at these early disease states.

They found that the tumours expanded preferentially in the brain’s white matter regions, which are rich in axons (long, thread-like extensions that connect nerve cells). The tumours compressed and injured the axons, triggering a process called Wallerian degeneration, in which SARM1 breaks down these damaged axons by destroying their source of energy (a molecule called NAD⁺).

This process, which increased inflammation in the brain, coincided with the tumours becoming more aggressive, suggesting they used the brain’s response to injury as fuel for their own growth.

The researchers found that inducing injury to axons in mice accelerated the progression of the tumour. They also found that, among mice whose SARM1 gene had been de-activated and whose axons did not get broken down so quickly, the tumours stayed in a less aggressive state.

Senior co-author Mr Ciaran Hill (UCL Cancer Institute and a consultant neurosurgeon at UCLH) said: “Our findings show that there is an early stage of this disease that we might be able to treat more effectively. By interfering with the brain’s response to injury before the disease becomes intractable, we can potentially change how tumours behave, locking them in a more benign state.”

The researchers said that this study opens up new areas of investigation linking brain cancer and neurodegeneration, and paves the way for future treatment strategies aimed at earlier intervention.

Gigi Perry-Hilsdon, Chair of The Oli Hilsdon Foundation, which raises funds for research into glioblastoma in loving memory of Oli*, said: “We know all too well the devastating statistics that currently exist in relation to glioblastoma, alongside the urgent need for better treatments.

“We are therefore immensely proud to have funded this pioneering research, led by Professor Simona Parrinello, in partnership with the Brain Tumour Charity. Her team’s unique approach to tackling this devastating disease at its early stages inspired us and gives hope that a breakthrough treatment is a possibility.” 

Research information manager at Cancer Research UK, Tanya Hollands, said: “Glioblastoma is a fast-growing type of brain tumour that’s difficult to treat, and people diagnosed with the disease face a poor prognosis.

“This fascinating research offers a fresh perspective on how glioblastomas grow and affect the brain. Uncovering how the brain’s response to damage may help fuel tumour growth opens a potential new avenue for treatment.

“While this work is still in its early stages and has so far only been demonstrated in mice, it lays important groundwork for developing treatments that could not only extend life, but also improve patients’ quality of life by preserving brain function for longer.”

*Gigi’s husband Oli was diagnosed with a glioblastoma at the aged of 22 and given less than 12 months to live. But he coped with his diagnosis with “optimism, courage and a wicked sense of humour”. He ran the London Marathon in under four hours, worked full time, travelled the world and got married. He died in January 2019, just 10 days before his 27th birthday. His family pledged to raise £1.5m towards Professor Parrinello’s research – and met their target a year early.  

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