MECHANISM OF PACLITAXEL NEUROTOXICITY

In discovering how certain chemotherapy drugs cause peripheral neuropathy, researchers at Dana-Farber Cancer Institute have found a potential approach to preventing this common and troublesome side effect of cancer treatment. Their findings were published by Pease-Raissi et al in Neuron.

The symptoms of peripheral neuropathy, which affects about one-third of patients receiving chemotherapy, include numbness, tingling, and pain in the hands and feet. Some patients improve after treatment ends, but in others, the symptoms are long-lasting. There is currently no preventive or treatment for peripheral neuropathy, which is caused by the degeneration of axons that transmit physical sensations to the brain. Unlike the brain, which is protected by a physical barrier from many harmful chemicals, nerve axons—which can extend as long as 2 or 3 feet in humans—are exposed to substances that flow through the blood circulation.

Study Findings

This new report reveals for the first time precisely how taxanes, a class of commonly used chemotherapy drugs, trigger a dying off of sensory axons. With this knowledge, it might someday be possible, the investigators say, to treat patients prior to chemotherapy that would reduce or prevent neuropathy symptoms.

Researchers led by Rosalind Segal, MD, PhD, discovered that a protein called Bclw plays a unique braking role in preventing the degeneration of nerve axons. Bclw blocks the action of another protein that sets off a cascade of chemical reactions ending in nerve cell death. Dr. Segal explained that Bclw is part of a regulatory system that allows unnecessary nerves to be “pruned” during embryonic development. During adult life, Bclw protects nerves from degeneration— except in the case of a traumatic injury or, in cancer treatment, exposure to chemotherapy drugs.

The gene carrying the blueprint for Bclw is located in the nucleus of the nerve cell. A carrier protein, SFPQ, transports copies of the Bclw blueprint in the form of messenger RNA along the nerve axon, where the protective Bclw protein is manufactured.

Dr. Segal and her colleagues found that adding a taxane—paclitaxel—to sensory nerve axons in the laboratory dramatically impeded the transport of Bclw messenger RNA by the SFPQ protein. As a result, too little of the Bclw protein was made to protect the axons, and they degenerated.

This finding led the investigators to ask if adding Bclw protein to the nerve axons before exposing them to paclitaxel would prevent the nerves from dying off—and it did. Moreover, they demonstrated that a synthetic compound based on a part of the Bclw protein—a so-called “stapled peptide” made in the laboratory of Dana-Farber researcher Loren Walensky, MD, PhD—was able to prevent degeneration from exposure to paclitaxel. This “designer peptide provides a promising template for drugs that can prevent chemotherapy-induced peripheral neuropathy,” said the scientists.

Such drugs aren't likely to become available any time soon, but Dr. Segal said having discovered the mechanism that causes peripheral neuropathy in patients treated with taxane chemotherapy might be valuable in other ways. “One possibility is that you might be able to predict which patients will develop peripheral neuropathy based on whether they have higher or lower levels of Bclw based on their genetic background,” she concluded.