Researchers Uncover Clues to Treatment for Chemotherapy-induced Peripheral Neuropathy

Chemotherapy can extend life, or even provide a cure, but occasionally with side effects so severe that patients reduce or discontinue treatment. Take the case of paclitaxel, an agent originally derived from the bark of the western yew tree, and one of the most common tools used to treat cancers of the ovary, breast, lung, and head and neck.

From left, at commencement, research team leader R. Grace Zhai, Ph.D., with first author Jennifer M. Brazill, Ph.D., whose dissertation described the findings that appeared in the journal article.

“Paclitaxel is one of the most active drugs used against ovarian cancer,” said Brian Slomovitz, M.D., co-leader of the Gynecologic Cancers Site Disease Group at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “Despite its life-saving effects, however, one of the side effects is peripheral neuropathy. Up to 50 percent of patients or more have some component of neuropathy, and in a large percentage it persists — even after treatment stops.”

But across the Miller School campus, a team of investigators in the Department of Molecular and Cellular Pharmacology appears to be in the early stages of finding a way to alleviate the discomfort patients like Slomovitz’s are experiencing. In the laboratory of Associate Professor R. Grace Zhai, Ph.D., a study led by former doctoral student Jennifer M. Brazill, Ph.D., has established a new in vivo animal model for chemotherapy-induced peripheral neuropathy (CIPN), uncovered a mechanism underlying neuropathy, and discovered a potential role for a neuroprotective factor in mitigating CIPN.

An article detailing their findings, “Nmnat Mitigates Sensory Dysfunction in a Drosophila Model of Paclitaxel-induced Peripheral Neuropathy,” was published online on June 12 by the journal Disease Models & Mechanisms, with Brazill as first author and Zhai as corresponding author, and another doctoral student, Yi Zhu, and an undergraduate student in the SURF (Summer Undergraduate Research Fellowship) program, Beverley Cruz, as co-authors. The article will also appear as the cover story in the journal’s June print issue, featuring a cover illustration depicting the reaction of nerve pathways to chemotherapy drugs.

“CIPN is the major dose-limiting side effect of many commonly used chemotherapeutic agents, including paclitaxel,” said Zhai. “Currently there are no neuroprotective or effective symptomatic treatments for CIPN, and lack of understanding of the in vivo mechanisms of CIPN has greatly impeded the identification of therapeutic agents.”

The researchers began by optimizing a model of paclitaxel-induced peripheral neuropathy using Drosophila (fruit fly) larvae that mimic aspects of CIPN sensory dysfunction. Studying the larvae, they identified activity that causes pain through stimulation of the nerve cells. They also identified a critical role for nicotinamide mononucleotide adenylyltransferase (Nmnat), an enzyme known to have neuroprotective properties.

“We found that it maintains the integrity and function of peripheral sensory neurons and has therapeutic potential against diverse sensory symptoms of CIPN,” said Zhai.

The next phase, she said, will be to use the model they developed to screen for therapeutic agents to treat CIPN.

“I congratulate these authors for uncovering evidence of a means to potentially reduce or eliminate this side effect,” said Slomovitz, who is also professor of clinical obstetrics and gynecology and director of the Division of Gynecologic Oncology. “While their study is preclinical in nature, it may lead us not only to improved outcomes, but also to improved quality of life with fewer side effects.”

The journal article summarized a significant part of the dissertation work of first author Brazill, who received her Ph.D. in molecular and cellular pharmacology in May.

The research was supported by the Sheila and David Fuente Neuropathic Pain Research Program Graduate Fellowship (University of Miami), the Lois Pope LIFE Foundation Fellows Program, the University of Miami SURF (Summer Undergraduate Research Fellowship) Program, and the National Institutes of Health (NIH)/NINDS R56NS095893.

Tags: Brian Slomovitz, Grace Zhai, Jennifer Brazill, paclitaxel, peripheral neuropathy