Scientists Discover a Probable Cause of "Chemo Brain" and It May Be Treatable
As anyone who has undergone cancer treatment will know, it comes with a host of unpleasant side-effects. From distressing hair loss to nausea to pain and mobility issues, every person with cancer has a different experience and many cancers are treated with a cocktail of chemotherapies.
But these side-effects are, regrettably, not confined only to people who are still on treatment. Many cancer survivors experience long-term, chronic effects from their treatment, which can last for the rest of their lives. One of the most frequently reported issues is that of ‘chemo brain,’ a difficult to pinpoint condition, the name coined by cancer survivors themselves, where survivors can report a range of symptoms, from feeling tired, disoriented, being forgetful and easily losing focus.
Now scientists at Stanford University may have figured out why a particular drug causes chemo brain and even better, they may be able to treat or even prevent it in the future. The drug, methotrexate has long been suspected of being responsible for some of the neurological side effects experienced by survivors and is used to treat a variety of cancer types, notably some types of breast cancer and childhood cancers. It works on cancer cells by starving them of folic acid which they need to replicate their DNA and grow but until now the details about how methotrexate might cause neurological symptoms were vague and speculative.
The research, published in the journal Cell, looked at the effect of methotrexate on three major types of nerve cell in the brain and spinal cord, collectively called glia. They are; astrocytes, which act as cellular scaffolding keeping everything in order, microglia, which act as immune system defense and oligodendrocytes, which produce a substance called myelin.
Myelin is a mixture of fats and proteins which insulate our central nervous system. Much like the plastic or rubber coatings on electrical wiring allow electricity to flow through it seamlessly, myelin stops our nerve signals from leaking out. However, when myelin becomes too thin or is missing in areas, these nerve impulses can fail to reach their destination causing a range of symptoms such as weakness and paralysis as happens in multiple sclerosis, when the immune system mistakenly attacks myelin.
“We took archival brain samples taken from children who had passed away from cancer after chemotherapy treatment and compared them to samples taken from children who hadn’t died of cancer. There was quite a prominent decrease of OPCs (immature oligodendrocytes) in the children and young adults who had chemotherapy,” said Michelle Monje, leader of the research, pediatric neuro-oncologist and Associate Professor of Neurology at Stanford University.
However, the children who these samples were from had been treated with a host of different chemotherapy drugs, making it difficult to pin down which one was responsible. Next, the team studied a brain sample from a child who had died from cancer who was treated with methotrexate and another child who had died from a brain tumor, but had no methotrexate. They found a substantially reduced number of OPCs in the brain exposed to methotrexate.
Next, the researchers used mice treated with methotrexate in a similar way to which children with cancer receive the drug to figure out exactly how the drug affected their oligodendrocytes and how this, in turn, affected their behavior They found that the mice treated with methotrexate had malfunctioning OPCs and also thinner myelin covering their nerves. The scientists also tested the performance of the mice on experiments designed to evaluate attention and memory, finding that the mice who had methotrexate showed deficits as well as exhibiting anxiety, another symptom often reported by cancer survivors…
The researchers were finding out more and more, but still hadn’t quite finished the puzzle. They delved in further and found that the methotrexate directly activated the microglial cells, creating knock-on effects that upset the function of the astrocytes and oligodendrocytes, leading to the disruption of myelin. The methotrexate had effectively barged in and disrupted a normally-harmonious relationship by causing the normally-peaceful microglial cells to go into overdrive.
“We looked to see whether microglia were directly affected by the methotrexate and found they were, but methotrexate did not directly affect the astrocytes – rather factors secreted by the microglia affect the astrocytes and oligodendrocytes,” said Monje.
The work has provided a major step forward in a field where methotrexate has been long-suspected but never proven to be a major cause of chemo brain.
“This is very nice work that indicates that nerve cells of mice experiencing a mimic of “chemobrain” are hurt by a cascade involving not one but all 3 major glial cell types. It starts with microglia, the brain’s immune cells, which activate the supporting astrocytes, culminating in lasting damage to the insulating wrappings of oligodendrocytes and their precursors in the brain’s white matter” said Dr Julien Muffat, head of the Laboratory for Synthetic Neuroimmunology at the Hospital for Sick Children in Toronto.
Reassuringly, there are experimental drugs available that can block the activation of microglia. The researchers tested one such drug, called PLX5622 in their mice who had been previously treated with methotrexate and found that it was able to suppress the microglia, allowing the myelin to return to normal. They put the mice through the barrage of cognitive testing again and found they were normal. The researchers gave the drug to the mice straight after chemotherapy, but it isn’t currently known whether it might have similar regenerative effects in people treated a long time ago.
“The overall goal is to be able to induce regeneration for people who have previously received chemotherapy. We need to find out when the therapeutic window is,” said Monje, explaining that work to investigate this is currently ongoing in her lab.
PLX5622 is one of several drugs currently in clinical trials which are a class of ‘CSF1R inhibitors’ that is, they target microglia. Over forty trials of CSF1R inhibitors are in progress for everything from cancer to rheumatological diseases. None are yet FDA-approved.
But what about people who have chemo brain after cancer treatment, but have never had methotrexate?
“Each cancer therapy needs to be studied in the laboratory in a focused way. There are some merging commonalities that might be relevant for why many cancer therapies cause neurological side effects. Microglial inflammation is involved with more than one therapy,” said Monje.
Previously, researchers have been confined to using single types of cells to study the effects of drugs on cells, both intended and unintended, but new ways of modeling healthy tissues, such as stem cells and organoids, together with ever-evolving methods to evaluate these models has meant that the effect of drugs can be studied on models that more-accurately recapitulate what occurs in people.
“As we go beyond animal models and turn to human brain-in-a-dish approaches, our own work suggests that cells should not be studied in artificial isolation. Clearly, our models must include all the key players, particularly the inflammation cascade-initiating immune cells and star-shaped astrocytes, if we want to understand the ultimate vulnerability of the wiring circuits,” said Muffat.
Biological investigations into the side-effects of cancer treatments are still fairly small in number, in comparison to the vast number of studies that look for new treatments, but this study and several others this year focused on cancer side-effects should be reassuring to survivors.
“It is going to be lots of work to see how each cancer therapy might cause side effects. We need to study each drug individually,” said Monje.