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Therapeutic Target Identified in Chemo Brain

Chemotherapy is a life-saving treatment for many patients with cancer. However, it can also leave patients with lasting neurological deficits through a condition commonly known as "chemo brain."

"It's wonderful that they're alive, but their quality of life is really suffering," commented Erin Gibson, PhD, a postdoctoral researcher at the Stanford University School of Medicine. "If we can do anything to improve that, there is a huge population that could benefit."

In a study published in Cell, Dr. Gibson and colleagues at Stanford Medicine have now identified the mechanisms behind this condition and found a potential therapeutic target that can counterbalance chemotherapy's detrimental effects on cognitive health.

The researchers found that humans who had undergone chemotherapy exhibited persistent depletion of oligodendrocyte lineage cells, which are important to the functioning of the brain's neural networks. In a mouse model of neurological dysfunction induced by methotrexate chemotherapy, the investigators found that white matter oligodendrocyte progenitor cells (OPCs) were similarly depleted. They also found increased OPC differentiation, but that differentiation was incomplete. In addition, the mice displayed a persistent deficit in myelination.

When the researchers transplanted OPCs from mice who had not experienced chemotherapy into the microenvironment of brains previously exposed to methotrexate, those OPCs also showed increased differentiation. This, the researchers concluded, indicates an underlying disturbance in the microenvironment.

The investigators found that methotrexate causes lasting activation of microglia; inflammatory microglia then cause the activation of astrocytes.

"The biology of this disease really underscores how important intercellular crosstalk is," noted Michelle Monje, MD, PhD, Associate Professor of Neurology and Neurological Sciences at Stanford Medicine and the study's senior author. "Every major neural cell type is affected in this pathophysiology." Commenting that this type of complex dysfunction may also underlie other cognitive disorders, she remarked, "I think that is probably more the rule than the exception."

The researchers did find a potential solution to this problem: depleting the microglia after methotrexate chemotherapy normalized the oligodendrocyte lineage cells and myelin microstructure, resulting in normalized cognitive behavior. Thus, inflammatory microglia would be a good therapeutic target to nullify cognitive impairment resulting from chemotherapy.

More research is needed, but Dr. Monje emphasized that this line of study could lead to results that could truly impact patients' lives: "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."

For More Information

Gibson EM, Nagaraja S, Ocampo A, et al (2018). Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell. [Epub ahead of print] DOI:10.1016/j.cell.2018.10.049

​Image credit: Rhoda Baer, National Cancer Institute

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