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.
View the paper at: Axonal injury is a targetable driver of glioblastoma progression | Nature
