A drug already in trials may stop chemotherapy nerve damage

Up to half of all individuals who receive chemotherapy develop chemotherapy-induced peripheral neuropathy (CIPN). This condition leads to tingling, numbness and pain in the hands and feet, and because effective treatments are limited, many patients must reduce or end their therapy early. The preclinical study, published Oct. 29 in Science Translational Medicine, points to possible ways to prevent or reduce CIPN and suggests that future blood tests could help identify patients most at risk.

"We uncovered a molecular mechanism that maps specifically to immune cells, not neurons," said co-senior author Dr. Juan Cubillos-Ruiz, the William J. Ledger, M.D. Distinguished Associate Professor of Infection and Immunology in Obstetrics and Gynecology at Weill Cornell Medicine. "This provides strong evidence that chemotherapy-induced neuropathy is not just a nerve issue but an immune-mediated inflammatory process driven by cellular stress responses."

The research was co-led by Dr. E. Alfonso Romero-Sandoval, professor of anesthesiology at Wake Forest University School of Medicine.

How a Cellular Stress Pathway Fuels Pain

Earlier work from Dr. Cubillos-Ruiz and colleagues showed that a pathway known as IRE1α-XBP1 acts like a molecular "alarm system" in immune cells, switching on when these cells are under stress. Their previous studies demonstrated that this pathway can drive pain after surgery and inflammation in mouse models.

For the new research, the team used a well-established mouse model that mirrors the nerve damage reported by chemotherapy patients. They found that paclitaxel, a commonly used chemotherapy drug, prompts immune cells to produce large amounts of reactive oxygen species, which are molecules that place cells under stress. This stress response turns on the IRE1α pathway, shifting immune cells into a highly inflammatory state.

These overstimulated immune cells then move toward the dorsal root ganglia -- the sensory nerve hubs that link the limbs to the spinal cord -- and release inflammatory compounds that irritate and damage nerves. This series of events produces classic CIPN symptoms: pain, sensitivity to cold and loss of nerve fibers.

Blocking the Stress Switch Lessens Nerve Damage

Using genetic tools to silence IRE1α in immune cells prevented the surge of inflammation and reduced CIPN-like behaviors in mice. The researchers also tested a drug that specifically blocks IRE1α and is already in phase 1 clinical trials for cancer. When mice received both chemotherapy and the IRE1α inhibitor, they showed fewer signs of pain typically associated with paclitaxel, and their nerves remained healthier.

"Our findings suggest that targeting IRE1α pharmacologically could mitigate neuropathy induced by taxanes, helping patients continue with their chemotherapy without the negative side effects of nerve damage," said Dr. Cubillos-Ruiz, who is also co-leader of the Cancer Biology Program at the Sandra and Edward Meyer Cancer Center at Weill Cornell.

Because IRE1α inhibitors are currently being tested in people with advanced solid tumors -- where excessive activity of this pathway can contribute to cancer growth and resistance to treatment -- the new results suggest these drugs might also shield patients from chemotherapy-related nerve injury. Dr. Cubillos-Ruiz noted that this potential dual action "could meaningfully improve both the effectiveness of cancer treatment and patients' quality of life."

Toward a Predictive Blood Test

To explore how the preclinical findings might apply to patients, the team conducted a small pilot study with women receiving paclitaxel for gynecologic cancers. Blood samples collected before and during each chemotherapy cycle revealed that those who later developed severe CIPN showed higher activation of the IRE1α-XBP1 pathway in their circulating immune cells, even before symptoms began.

This early signal suggests that a blood test could eventually help identify patients who are more likely to develop neuropathy, opening the door to preventive steps -- potentially including IRE1α inhibitors -- before nerve damage sets in.

This research was supported by the National Cancer Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health, as well as the U.S. Department of Defense.