Answers to important questions:
Q: What causes nerve damage from chemotherapy?
A: The stress response in immune cells, triggered by the IRE1α sensor, causes inflammation that damages nerves.
Question: How did scientists demonstrate this relationship?
A: By blocking IRE1α in mice, researchers were able to prevent pain and nerve damage. The same molecular pattern was seen in patients who developed neuropathy.
Q: What does this mean for cancer treatment?
A: This could lead to drugs that protect patients from nerve pain, without affecting the anti-cancer effects of chemotherapy.
Summary: A new study shows that chemotherapy-induced neuropathic pain is caused by a stress response in immune cells that triggers inflammation and neurotoxicity. The researchers found that activating a cellular stress sensor called IRE1α causes nerve damage and pain during chemotherapy, but blocking it prevents both effects in mice.
Patients with high IRE1α activity also experienced more severe neuropathy, confirming this association in humans. The finding points to a promising new therapeutic target that could protect cancer patients from the most distressing side effects of life-saving treatments.
Key data
- Cause identified: Chemotherapy activates the IRE1α stress sensor in immune cells, leading to inflammation and nerve damage.
- Potential prevention: Blocking IRE1α in mice completely prevented pain and nerve damage, suggesting a therapeutic approach.
- Clinical context: Cancer patients with high IRE1α activation were more likely to develop severe neuropathy.
Source: Wake Forest University
Scientists at Wake Forest University School of Medicine, working with researchers at Weill Cornell Medicine, have made major progress in understanding why many cancer patients experience nerve damage after chemotherapy.
Their new research suggests that a stress response in certain immune cells may cause this debilitating side effect. The discovery could open the door to new ways to prevent or treat nerve damage in cancer patients.
The research findings were published online today in the journal Science Translational Medicine.
Chemotherapy-induced peripheral neuropathy is a common and often serious side effect of cancer treatments, especially those containing paclitaxel. It can cause tingling, numbness, and pain in the hands and feet, sometimes forcing patients to stop life-saving treatments prematurely.
About half of all patients receiving chemotherapy develop this condition. However, the exact cause remains a mystery.
To better understand this neurotoxicity, which can be painful, the scientists used a proven mouse model that closely resembles the neurological problems experienced by people undergoing cancer treatment. This model allowed the researchers to observe how a specific immune cell pathway, called IRE1α, contributes to the inflammation that leads to neurotoxicity and pain.
By blocking the IRE1α pathway in the immune cells of these mice, using either genetic techniques or an IRE1α inhibitor, the team was able to prevent the development of nerve damage, pain, and toxic inflammation.
The researchers also studied a group of patients at Atrium Health Wake Forest Baptist National Cancer Institute’s designated comprehensive cancer center.
The patients were receiving chemotherapy for gynecological cancer and blood samples were taken before and after treatment to measure IRE1α activity in their immune cells.
They discovered that patients with higher IRE1α activation were more likely to develop severe neuropathy as a result of chemotherapy. This allowed them to directly link the results of the mouse model to patient outcomes.
Key findings
- Chemotherapy activates stress sensors (IRE1α) in immune cells, causing inflammation and nerve damage.
- By blocking this sensor in mice, pain and nerve damage can be prevented, suggesting that it could be a new therapeutic target.
- In patients, greater activation of this stress sensor in blood cells was also associated with more severe neurological symptoms and the development of neuropathic symptoms.
“Our research shows that the stress response within immune cells is a key factor in chemotherapy-induced neuropathy, which can be painful and debilitating. By targeting this pathway, we could protect patients from one of the most difficult side effects of cancer treatment,” said Dr. E. Alfonso Romero-Sandoval, Professor of Anesthesiology at the University of California, Berkeley and Lead of the School of Anesthesiology.
“Our research provides an opportunity to further investigate whether this pathway can be used to predict which patients will develop this condition, thus helping doctors implement personalized treatments for each patient,” Romero-Sandoval said.
This discovery could lead to new drugs that block this pathway, allowing patients to continue cancer treatment without painful side effects.
According to Romero-Sandoval, a member of Atrium Health Wake Forest Baptist Comprehensive Cancer Center, this is the first study to show that the IRE1α stress sensor in immune cells is directly linked to chemotherapy-induced nerve damage.
The team plans to conduct larger clinical studies to confirm and test these findings to see whether the IRE1α pathway can be used as a biomarker for disease progression and whether drugs that block this stress sensor can safely prevent or reduce nerve damage in cancer patients.
They also hope to investigate whether this approach could be useful for other types of neuropathic pain. Interestingly, clinical trials are underway for IRE1a inhibitors to enhance the anti-cancer effects of chemotherapy, including paclitaxel.
Funding: 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. It also received additional support from Atrium Health Wake Forest Baptist Comprehensive Cancer Center.
About this neurology and cancer research news
Author: Myra Wright
Source: Wake Forest University
Contact: Myra Wright – Wake Forest University
Image: The image is credited to StackZone Neuro
Original Research: Closed access.
“Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy” by E. Alfonso Romero-Sandoval et al. Science Translational Medicine
Abstract
Leukocyte inner endoplasmic reticulum stress responses contribute to chemotherapy-induced peripheral neuropathy.
Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and debilitating side effect of paclitaxel treatment in cancer patients. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells detect and interpret systemic exposure to paclitaxel during treatment is not yet fully understood.
Here, we found that paclitaxel administration activated the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) in circulating and dorsal root ganglion resident myeloid cells, creating an inflammatory environment that promoted CIPN.
From a mechanistic perspective, paclitaxel induced overproduction of mitochondrial reactive oxygen species (ROS), which led to endoplasmic reticulum stress and hyperactivation of IRE1α in macrophages.
, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2 are produced by IRE1α.
Depletion of IRE1α in leukocytes or treatment with a selective pharmacological inhibitor of IRE1α prevented dorsal root ganglion neuroinflammation and CIPN-related pain behavior in mice.
Furthermore, the development and severity of CIPN in patients with gynecological cancer appears to be associated with the activation status of IRE1α in their circulating leukocytes.
Our research suggests that leukocyte-intrinsic IRE1α is a key mediator of CIPN. We suspect that addressing its dysregulated activation may help reduce CIPN in cancer patients receiving paclitaxel.
