Strategy to prevent chemotherapy-induced neuropathy

Platinum drugs such as cisplatin are among the most widely used chemotherapy medications. However, approximately 40 percent of cancer patients treated with platinum drugs develop chemotherapy-induced peripheral neuropathy — generally involving loss of feeling or intense, burning or tingling pain in the feet.

To date, this side effect is unpreventable and can limit chemotherapy dosage for patients with cancer. Protective strategies are complicated by the possibility that preventing peripheral neuropathy might inhibit the cancer-fighting properties of the chemotherapy drug. That problem might be avoided if a protective agent were neuron targeted and delivered directly into the nervous system.

Researchers at Mayo Clinic in Rochester, Minnesota, have shown the potential of mesenchymal stem cells to act as therapy for nervous system diseases by carrying extracellular products across the blood-brain barrier. In studies of potential treatments for patients with amyotrophic lateral sclerosis (ALS), the researchers have demonstrated the safety of this strategy, with no significant adverse effects observed in 43 patients. Now, the researchers propose to use stem cells to deliver nerve protection into patients' nervous systems before chemotherapy starts.

"We have recently discovered in the laboratory a compound that seems to be quite potent in protecting the nerve cell damage that cisplatin produces," says Anthony J. Windebank, M.D., a consultant in Neurology at Mayo Clinic in Rochester, Minnesota. "We're proposing to take stem cells from a patient's adipose tissue and use genome-editing technology to put this new compound into the stem cells. Then we would inject the stem cells into the patient's cerebral spinal fluid, as a means of placing this compound into the central nervous system without its getting into the way of the cancer in the lungs, ovaries or breast."

Re-engineering stem cells

Through the Mayo Clinic Center for Regenerative Medicine, Dr. Windebank has directed several studies involving the use of stem cells to promote nerve generation. "From our ALS studies, we know that these stem cells are very safe and last probably three to six months in the nervous system after injection," he says. "Most chemotherapy is given over a three- to four-month period, so we hope the protective strategy for neuropathy would cover patients throughout their cancer treatments."

In more than 20 years of research on chemotherapy-induced neuropathy, Dr. Windebank and colleagues have shed light on the mechanisms by which platinum drugs damage neurons. Dorsal root ganglion neurons are the primary target.

"Cisplatin actually causes the death of the neuron, not just nerve endings," Dr. Windebank says. "Cisplatin neuropathy also has the unusual characteristic of continuing to worsen for two or three months after chemotherapy ends, which is why oncologists are very careful to cut back chemotherapy dosage when patients begin to develop neuropathy."

Although chemotherapy-induced neuropathy can ease somewhat, most patients have residual symptoms years after cancer treatment ends. "Cancer treatment has improved phenomenally. The majority of people who have cancer are either cured or have long-term survival," Dr. Windebank notes. "I see people who, 20 years after their cancer is cured, have almost forgotten they had it. But they're still dealing with peripheral neuropathy that impairs their quality of life. By pursuing this strategy, we hope eventually to take cells that don't normally get into the nervous system, give them some extra bullets with genetic engineering and then prevent chemotherapy-induced neuropathy."