Scientists Find Possible Antidote for Tamoxifen-Induced Mental Fog
Researchers from University of Rochester Medical Center have shown scientifically what many women report anecdotally: that tamoxifen is toxic to cells of the brain and central nervous system (CNS), producing mental fogginess similar to “chemo brain.” In the study, published in the Journal of Neuroscience, the researchers also report the discovery of an existing drug compound that appears to counteract or rescue brain cells from the adverse effects of the breast cancer drug.
Corresponding author Mark Noble, PhD, Professor of Biomedical Genetics and Director of the University of Rochester Stem Cell and Regenerative Medicine Institute, commented that it is exciting to potentially be able to prevent a toxic reaction to one of the oldest and most widely used breast cancer medications on the market. Although tamoxifen is more easily tolerated compared to most cancer treatments, it nonetheless produces troubling side effects in a subset of the large number of people who take it.
By studying tamoxifen’s impact on central nervous system cell populations and then screening a library of 1,040 compounds already in clinical use or clinical trials, Dr. Noble’s team found that the investigational MEK1/2 inhibitor selumetinib (also known as AZD6244 essentially eliminated tamoxifen-induced killing of brain cells in mice.
The research is the result of two separate but related projects from Dr. Noble’s lab. One investigates the science underlying the 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.
Study Details
In the Journal of Neuroscience paper, Dr. Noble’s team first identified CNS cells that are most vulnerable to tamoxifen toxicity. Chief among these were oligodendrocyte-type 2 astrocyte progenitor cells (O-2A/OPCs), which are essential for making the insulating sheaths, or myelin, required for nerve cells to work properly. Exposure to clinically relevant levels of tamoxifen for 48 hours killed more than 75% of these cells.
“It’s critical to find safe treatments that can rescue the brain from impairment,” Dr. Noble said, “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.”
Dr. Noble’s lab, led by postdoctoral fellow Hsing-Yu Chen, PhD, identified 27 drugs that protected O-2A/OPCs from the effects of tamoxifen. Further testing by other laboratories resulted in singling out selumetinib as a potential cancer therapy.
In mice cotreated with tamoxifen plus selumetinib, cell death in the corpus callosum, was prevented, the paper reported. Meanwhile, several national clinical trials are testing the safety and effectiveness of selumetinib in treating multiple cancers, from breast and colon to melanoma and lung.
Drug Enhances Targeting of Cancer Cells
Researchers were also optimistic about finding that while selumetinib 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 the studies in Dr. Noble’s lab found that the combined use of selumetinib and chemotherapy enhanced targeting of cancer cells.
“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,” said Dr. Noble, who also collaborates with researchers at the University of Rochester's James P. Wilmot Cancer Center. “This creates a whole new paradigm; it’s where we need to go.”
In future work, Dr. Noble’s group plans to identify the dosage of selumetinib that provides maximum protection and minimum disruption to differentiating brain cells.
The research research was supported by the U.S. Department of Defense, National Institutes of Health, Susan Komen Race for the Cure, and the Carlson Stem Cell Fund.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
