- Life expectancy after diagnosis with cancer has increased in recent decades, due to advances in treatments.
- Many people who have had cancer treatment experience the side effects from chemotherapy, including cognitive effects dubbed “chemo brain.”
- A new study has proposed a new mechanism underpinning chemo brain, and identified an existing drug that could be repurposed to treat it.
Over half of people who receive a cancer diagnosis now can expect to live over a decade after this diagnosis, largely due to improvements in cancer treatments.
However, treatment for cancer includes surgery, radiotherapy, and chemotherapy, all of which can cause damage to the body while fighting cancerous cells. These treatments can therefore have mental and physical health consequences for patients that can last for years after treatment has stopped.
The cognitive effects of chemotherapy are well known and can be debilitating for some, earning it the moniker “chemo brain.” Estimates suggest that as many as half of the people who undergo chemotherapy experience this side effect.
“Chemo brain is a really good example where I’ve had patients say to me, ‘you know, I’m really glad you cured [me].’ But this chemo brain is so bad, it really makes me question, was it all worth it?’ And that’s hard to hear, right? Because what you’re hearing is people saying, ‘I’m glad I’m alive but at the same time, my life is so different now. Am I sure, it was all worth it?'”
– Dr. Arif Kamal
As with many cognitive problems, it has been unclear what underpins chemobrain, making it difficult to identify and design drug treatments, until now.
A team of researchers at Saint Louis University, MO, has uncovered a potential mechanism behind the neuroinflammation and oxidation that could lead to chemo brain. They say the identification of this mechanism could also point to a potential drug treatment.
Their findings appear in the Journal of Clinical Investigation.
Phospholipids are an important part of the cell as they make up the cell and mitochondrial membrane, and sphingolipids are a particular type of lipid that is found in higher concentrations in the cells that make up the central nervous system, including the brain.
Previous research by the team had found that disruption to the production of sphingolipids caused by two different types of chemotherapy contributed to the neuropathic pain experienced by cancer patients.
Therefore for this study, the researchers looked at the effect of the chemotherapy drug cisplatin, which is used for a number of cancers, on sphingolipid production in mice.
They found that cisplatin treatment increased levels of an enzyme involved in the production of sphingolipid and therefore a metabolic intermediary, which acts as a potent signaling molecule sphingosine-1-phosphate (S1P). S1P can bind to a specific receptor in the cell that is involved in a wide range of cellular pathways and is already known to play a role in a number of inflammatory and neurological diseases.
The authors hypothesized that an increase in the amount of S1P binding to receptors leads to mitochondrial dysfunction, which in turn leads to oxidative stress and inflammation.
The researchers observed that the mice they treated with cisplatin and a functional antagonist to this receptor that S1P binds to, had no adverse effects on the animals’ health. This showed that blocking the ability of the increased S1P to bind to specific receptors that lead to inflammation were not triggered, and the cognitive effects of the chemotherapy drug could be blocked.
Luckily, there are already two drugs that work as functional antagonists on the receptor in question, and they have already been approved by the Food and Drug Administration (FDA) for use in people with multiple sclerosis (MS): fingolimod and ozanimod.
This was just the first step to finding a pharmacological intervention that could be used to treat affected patients, said Prof. Daniela Salvemini, lead author, and William Beaumont professor of pharmacology and physiology at the University of St Louis. She told MNT that she wanted to “build on a story.”
Dr. Salvemini and her team’s previous work has looked at the role of sphingolipids on neuropathic pain.
“The ultimate goal is to provide the pharmacological rationale, to go into clinical trials with one of these already FDA approved drugs for the treatment of cognitive deficit in patients that will receive chemotherapy, or in patients that have received chemotherapy and have developed symptoms. So, we want to see whether we can prevent and treat. [T]hat’s really the long-term objective.”
– Prof. Daniela Salvemini
The team recently received news that it has been awarded a $2.3 million 5-year grant to build on this finding. Prof. Salvemini told MNT that she hoped to explore whether other forms of chemotherapy caused cognitive issues through the same mechanism, and whether the drugs could be repurposed not only to treat chemo brain, but to prevent it.
Earlier this year a paper published in Cell by researchers from Stanford University showed that the damage to brain tissue sustained by people who had SARS-CoV-2 infections and developed long COVID is similar to the brain damage seen in people with chemo brain.
Prof. Salvemini has also applied for a grant to investigate whether there could be any application for the drug for these patients too.