"It's critical to find safe treatments that can rescue the brain from impairment," Mark Noble says, "because despite increasing awareness and research in this area, some people continue to endure short-term memory loss, mental cloudiness, and trouble concentrating." (Credit: Maureen Didde/Flickr)

Compound clears cancer drug’s ‘mental fog’

An existing drug compound appears to eliminate the nasty side effect of a breast cancer drug that causes a mental fog similar to “chemo brain.”

Tamoxifen is one of the oldest and most widely used breast cancer medications on the market. While it is more easily tolerated compared to most cancer treatments, it is toxic to cells of the brain and central nervous system and produces troubling side effects for many people who take it.

By studying tamoxifen’s effect on central nervous system cell populations and then screening a library of 1,040 compounds already in clinical use or clinical trials, researchers identified a substance known as AZD6244. They showed that it essentially eliminated tamoxifen-induced destruction of brain cells in mice.

“As far as I know, no one else has discovered an agent that singles out and protects brain and central nervous system cells while also not protecting cancer cells,” says Mark Noble, professor of biomedical genetics and director of the Stem Cell and Regenerative Medicine Institute at the University of Rochester. “This creates a whole new paradigm; it’s where we need to go.”

The research is the result of two separate but related projects from Noble’s lab. One investigates the science underlying a condition known as “chemo brain,” and another is looking at how to exploit tamoxifen’s attributes for use in other types of cancer besides early-stage, less-aggressive breast cancer.

Tamoxifen is a type of hormonal therapy, which works by stopping the growth of estrogen-sensitive tumors.

In the study, published in the Journal of Neuroscience, Noble’s team first identified central nervous system (CNS) cells that are most vulnerable to tamoxifen toxicity.

Chief among these were oligodendrocyte-type 2 astrocyte progenitor cells (O-2A/OPCs), cells that are essential for making the insulating sheaths (called myelin) required for nerve cells to work properly. Exposure to clinically relevant levels of tamoxifen for 48 hours killed more than 75 percent of these cells.

In earlier work, while studying the biology of the cognitive difficulties that linger in some people being treated for cancer, Noble and colleagues discovered that 5-fluorouracil, (cisplatin, cytarabine, carmustine), and multiple other types of chemotherapy, damages populations of stem cells in the CNS.

Published in the Journal of Biology in 2006 and 2008, these studies pioneered analysis of the biological foundations of chemo brain.

“It’s critical to find safe treatments that can rescue the brain from impairment,” Noble says, “because despite increasing awareness and research in this area, some people continue to endure short-term memory loss, mental cloudiness, and trouble concentrating.

“For some patients the effects wear off over time, but others experience symptoms that can lead to job loss, depression, and other debilitating events.”

Other cancers, too

Noble’s lab, led by post-doctoral fellow Hsing-Yu Chen, identified 27 drugs that protected O-2A/OPCs from the effects of tamoxifen. Further testing resulted in singling out AZD6244, by other laboratories as a potential cancer therapy.

In mice co-treated with tamoxifen plus AZD6244, cell death in the corpus callosum, the largest white matter (myelinated) structure in the brain, was prevented. Meanwhile, several national clinical trials are testing the safety and effectiveness of AZD6244 in treating multiple cancers, including breast, colon, melanoma, and lung.

Researchers were also optimistic about finding that while AZD6244 protected brain cells, it did not also protect cancer cells. New drug compounds have greater value if they do not compromise the effects of existing treatments, and in this case, the experiments agreed with studies by other research groups that found that the combined use of AZD6244 and chemotherapy enhances targeting of cancer cells.

In future work, Noble’s group plans to identify the dosage of AZD6244 that provides maximum protection and minimum disruption to differentiating brain cells. The research was supported by the US Department of Defense, National Institutes of Health, Susan Komen Race for the Cure, and the Carlson Stem Cell Fund.

Source: University of Rochester

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