Repurposed Drugs Show Promise to Treat Chemotherapy-Induced Peripheral Neuropathy

Diabetes and multiple sclerosis drugs produce positive results in animal models, are poised for human testing

by Abdul-Kareem Ahmed on 12 Aug 2014

One of the most common reasons cancer patients stop chemotherapy early is because of a single side effect, chemotherapy-induced peripheral neuropathy (CIPN). Characterized by a gradual destruction of sensory nerves of the extremities, CIPN results in a combination of tingling, numbness, shooting and burning pain, and sensitivity to temperature. There is currently no way to prevent CIPN, but two recent studies demonstrate that FDA-approved drugs already in use for other purposes provide protection against the condition in mouse models. The studies open up a fast track to clinical testing of potential new treatments for a debilitating and ultimately life-threatening complication of cancer therapy.

A two-pronged approach

In searching for the biological underpinnings of chronic pain, researchers have focused on DNA, the proteins and enzymes it encodes, and finally the metabolites those enzymes affect. Recently, data have pointed to the central role of these metabolites, in particular, the pro-inflammatory sphingomyelin/ceramide pathway (see PRF related news story). Over the past five years, Daniela Salvemini, a pharmacologist and physiologist at St. Louis University School of Medicine, Missouri, US, and her team have delineated how sphingosine-1-phosphate (S1P), a derivative of ceramide, activates the S1P receptor type 1 (S1PR1) in dorsal horn neurons in the spinal cord and peripheral sensory neurons, sensitizing them and initiating a cellular cascade that results in neuropathy, neuroinflammation, and pain (for a review, see Salvemini et al., 2013).

Interestingly, production of ceramide is part of the main mechanism of cell death induced by cancer chemotherapeutic agents, providing a possible route to CIPN—in the course of killing tumor cells, a chemotherapeutic agent may also boost production of S1P and activate pain pathways.

For the first time, in a study published May 29 in the Journal of Biological Chemistry, Salvemini and colleagues report that S1P, acting via S1PR1, is critical for triggering symptoms of CIPN in a rat model treated with the taxane paclitaxel, a first-line chemotherapy treatment for breast and other cancers, or oxaliplatin, a treatment for colorectal cancer.

That was exciting because there are several marketed drugs that target S1P action at its receptor. FTY720 (also called fingolimod) was approved by the FDA in 2010 for the treatment of multiple sclerosis (MS) and is a potent functional antagonist of S1PR1. “As soon as we found that S1PR1 is involved, we tested FTY720,” Salvemini said.

In the study, lead author Kali Janes and coworkers found that FTY720 could prevent or reverse the signs of neuropathic pain in the rats without diminishing the anti-cancer properties of paclitaxel or oxaliplatin.

Based on these results, “Clinical evaluation of this compound needs to happen fast,” said Salvemini. “We have a drug that is already used in MS patients for several years now that could be translated for chronic neuropathic pain states, like CIPN.”

By repurposing FTY720, any of its second-generation compounds being tested for MS could be tested for CIPN as well. Additionally, FTY720 itself is being tested as an anti-cancer agent, as it blocks anti-apoptotic actions of S1P. The hope is that while preventing CIPN, clinicians could also enhance the anti-cancer effects of chemotherapeutic agents—a dual-pronged approach (Zhang et al., 2013).

“It’s a finding that can’t be put on the side,” Salvemini said.

Salvemini told PRF her team at St. Louis University will be initiating clinical trials of FTY720 for CIPN specifically. In addition, the group is already conducting rat studies to determine if FTY720 reduces peripheral neuropathy induced by other common chemotherapeutic agents.

More dual action

For cancer patients, hope for CIPN might lie in another familiar drug. Metformin is a widely used, FDA-approved anti-diabetic drug. For type 2 diabetics, it stabilizes blood glucose levels and reduces blood lipid levels.

Cobi Heijnen, a neuroimmunologist at the University of Texas M.D. Anderson Cancer Center, Houston, US, recognized metformin’s potential after Theodore Price and his team, then at the University of Arizona, Tucson, US, demonstrated that metformin prevented neuropathic pain in rodent models of nerve injury (Melemedjian et al., 2013).

In a study published in PLoS One in June, first author Qi-Liang Mao-Ying and coworkers reported that administration of metformin before cisplatin in mice prevented mechanical allodynia, sensory deficits, and loss of peripheral nerve fibers. Metformin also reversed mechanical allodynia induced by paclitaxel.

“Since metformin is the most frequently prescribed drug and is very inexpensive, it could become of great use, provided the drug also works in humans to prevent chemotherapy-induced neuropathy,” said Heijnen.

Metformin impacts mitochondrial respiration, leading to the activation of adenosine monophosphate-activated protein kinase (AMPK), which potentially has a neuroprotective effect in the peripheral nervous system (for more on this topic, see PRF related webinar). Through the same mechanism, metformin itself may also have anti-cancer properties—studies suggest the drug decreases the lifetime risk of cancer in diabetics by 30 percent (Decensi et al., 2010).

Like FTY720, metformin could potentially decrease the dose-limiting side effects of chemotherapy and also act to enhance the anti-tumor activity of chemotherapeutic agents.

“Since metformin is already being tested in clinical trials for its potential anti-cancer effect, it should not be difficult to run additional trials focusing on prevention of CIPN,” said Heijnen.

Cautious optimism

“Having these drugs that have already been given to people minimizes the obstacles for FDA approval,” said Sara Ward, a pharmaceutical scientist at Temple University, Pennsylvania, US. Ward works on new approaches to treating CIPN and recently demonstrated the efficacy of the cannabis derivative cannabidiol in a mouse model of paclitaxel-induced CIPN (Ward et al., 2014).

Although FTY720 and metformin are already FDA approved and show potency in these preclinical studies, “One of the big questions that’s unanswered right now is, Are our animal models of CIPN going to be predictive of something that will work in the clinic?” said Ward.

For more on CIPN and the latest research toward new treatments, see PRF related news story.

Abdul-Kareem Ahmed is a medical student and freelance science writer in Providence, Rhode Island, US.

Image credit:©iStockphoto.com/gemphotography