CIRM-funded research is helping unlock the secrets behind “chemo brain”

chemo brain

Every year millions of Americans undergo chemotherapy. The goal of the treatment is to destroy cancer, but along the way more than half of the people treated lose something else. They suffer from something called “chemo brain” which causes problems with thinking and memory. In some cases it can be temporary, lasting a few months. In others it can last years.

Now a CIRM-funded study by researchers at Stanford has found what may be behind chemo brain and identifying potential treatments.

In an article on the Stanford Medicine News Center, senior author Michelle Monje said:

“Cognitive dysfunction after cancer therapy is a real and recognized syndrome. In addition to existing symptomatic therapies — which many patients don’t know about — we are now homing in on potential interventions to promote normalization of the disorders induced by cancer drugs. There’s real hope that we can intervene, induce regeneration and prevent damage in the brain.”

The team first looked at the postmortem brains of children, some of whom had undergone chemotherapy and some who had not. The chemotherapy-treated brains had far fewer oligodendrocyte cells, a kind of cell important in protecting nerve cells in the brain.

Next the team injected methotrexate, a commonly used chemotherapy drug, into mice and then several weeks later compared the brains of those mice to untreated mice. They found that the brains of the treated mice had fewer oligodendrocytes and that the ones they had were in an immature state, suggested the chemo was blocking their development.

The inner changes were also reflected in behavior. The treated mice had slower movement, showed more anxiety, and impaired memory compared to untreated mice; symptoms that persisted for up to six months after the injections.

As if that wasn’t enough, they also found that the chemo affected other cells in the brain, creating a kind of cascade effect that seemed to amplify the impaired memory and other cognitive functions.

However, there is some encouraging news in the study, which is published in the journal Cell. The researchers gave the treated mice a drug to reverse some of the side effects of methotrexate, and that seemed to reduce some of the cognitive problems the mice were having.

Monje says that’s where her research is heading next.

“If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment. It’s an exciting moment.”

 

Clever Stem Cells Withstand Chemo Drug’s Harmful Side Effects

For some conditions, it seem that the treatment can cause almost as many problems as than the disease itself. That’s often the case with some forms of cancer, such as acute lymphoblastic leukemia.

The most common type of cancer to affect children, treatment usually involves chemotherapy with the drug methotrexate (MTX). And, while effective at destroying the deadly cancer cells circulating in the patients’ blood, it also does significant damage to another part of the body: the bone.

Scientists have long sought a method that helps patients recover more quickly from the harmful effects of chemotherapy.

Scientists have long sought a method that helps patients recover more quickly from the harmful effects of chemotherapy.

But new research from Brown University’s Dr. Eric Darling and his team has found that not all types of bone cells are equally at risk of being damaged by MTX. In fact, one type may actually be impervious to the drug’s negative effects. These findings, published last week in the journal Experimental Cell Research, are especially important as doctors look to ways that help the youngest, most vulnerable cancer patients heal faster after treatment—regaining bone strength that can take them into a healthy adulthood.

As Olivia Beane, a graduate student in the Darling Lab and the lead author of this paper, explained in a news release:

“Kids undergo chemotherapy at such an important time when they should be growing, but instead they are introduced to this very harsh environment where bone cells are damaged with these drugs. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

The cell type Beane is referring to are called adipose-derived stem cells, or ASCs, which normally mature from this early, stem cell state into several types of mature cells, including bone tissue. Initially, Beane had been researching the basic properties of ASCs. But during her experiments she discovered that ASCs, unlike other stem cell types that mature into bone, appear to survive MTX. Now they just needed to understand why.

Further experiments revealed the underlying strengths of ASCs in resisting MTX’s effects. Normally, MTX works by binding to and shutting down a protein in the cell called dihydrofolate reductase, which is normally involved in synthesizing DNA. With DNA production shut down, cells can’t divide and multiply—which is great for killing harmful cancer cells, but potentially harmful as it can also destroy cells it shouldn’t.

However, ASCs are a little bit different. When coming into contact with MTX, these cells ramp up the DNA-promoting dihydrofolate reductase, producing more than enough to overcome a normal dose of MTX.

This discovery has raised some intriguing possibilities for treating MTX’s side effects. As Darling explained:

“Chemotherapies do a great job of killing cells and killing the cancer, and that’s what you want. But then there is a stage after that where you need to do recovery and regeneration.”

And while the results of this study are preliminary, the researchers are cautiously optimistic that the MTX-resistant properties of ASCs could be the key to fast tracking recovery times.

The first step, Darling adds, is to save a life. And MTX has done that for countless children afflicted by cancer. But the cost of saving that life should also be taken into account—so that these children who have already been through so much may one day not need to worry about long, healthy lives as they mature into adults.

Want to learn more about how CIRM-funded researchers are developing new tools to fight all types of leukemia? Check out our Leukemia Fact Sheet.

Anne Holden