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Researchers at VCU Massey Cancer Center were awarded more than $1.1 million to investigate alternative treatment options for cancer patients with nerve damage, a debilitating side effect caused by chemotherapy.

M. Imad Damaj, Ph.D., member of the Cancer Prevention and Control research program at Massey, and David A. Gewirtz, Ph.D., member of Massey’s Developmental Therapeutics research program, received a four-year R01 grant from the National Cancer Institute to conduct research as a means to inform novel therapies that can prevent or suppress nerve damage triggered by paclitaxel.

Paclitaxel is a chemotherapy drug, often sold under the brand name Taxol, commonly used to treat breast, lung and ovarian cancer. One of the most common and serious side effects for cancer patients treated with paclitaxel is chemotherapy-induced peripheral neuropathy (CIPN), a form of nerve damage in the hands or feet that can generate severe pain or affect a person’s ability to complete basic motor skills such as walking or writing. Between 20 to 30 percent of cancer patients treated with taxanes (paclitaxel is a type of taxane) and platinum-based chemotherapy drugs develop CIPN, which may persist for months or years after treatment ends, according to the National Cancer Institute. CIPN can also be a dose-limiting factor in that the symptoms are sufficiently severe to prevent continuation of that form of chemotherapy. This can lead to premature termination of treatment, reducing drug effectiveness and the patient’s overall quality of life.

“The current therapies that are available are frequently ineffective in mitigating the painful symptoms of CIPN in the majority of cancer patients. Therefore, the identification of alternative forms of therapy is a crucial medical need,” Damaj said.

Damaj and Gewirtz, co-principal investigators on the project and professors of pharmacology and toxicology at the VCU School of Medicine, will focus on chemical compounds that activate a specific protein, called peroxisome proliferator-activated receptor alpha (PPARa), involved in pain transmission and other inflammatory responses. These compounds could potentially be used as complementary therapies to minimize or prevent the onset of CIPN caused by paclitaxel (as well as platinum-based therapeutics and drugs such as bortezimob).

Their research will seek to determine if the common cholesterol medication fenofibrate (often branded as Tricor or Triglide) and other drugs with similar chemical properties effectively prevent, reverse or reduce CIPN in mouse models treated with paclitaxel. Using cells in culture, patient-derived tumor cells and mouse models, Damaj and Gewirtz will then test the same drugs’ effects on the growth of non-small cell lung cancer cells as well as breast cancer cells and their susceptibility to paclitaxel. This is critical if cancer patients are to be given these drugs before or in conjunction with chemotherapy.

“If effective treatment or prevention for CIPN can be identified, it should be possible to extend the treatment of cancer patients with drugs such as paclitaxel and platinum-based compounds because dose-dependent neuropathy will no longer limit the utility of these therapies,” Gewirtz said.

This is the second grant that Damaj and Gewirtz have been awarded for efforts to mitigate CIPN. They are in the fourth year of a similar award through NCI’s Provocative Questions Program where they are studying a class of compounds derived from nicotine, known as nicotinic acetylcholine receptor agonists, to prevent or reverse CIPN. This work has led to the design of a clinical trial using nicotine patches to treat patients who have been cured of cancer but who are still suffering from the reduced quality of life caused by residual peripheral neuropathy.

Written by: Blake Belden