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Treatments in development for narcolepsy may reduce chemotherapy-induced fatigue

Uncovering the cause of fatigue represents a turning point in identifying possible therapies to counteract this debilitating side effect

Fatigue brought on by chemotherapy may be reversed with orexin, a brain protein that regulates arousal and sleep, according to a study led by an investigator with the Knight Cancer Institute at Oregon Health & Science University (OHSU).

The study, published in Brain, Behavior, Immunity, found that chemotherapy disrupts orexin neurons in the brain. Orexin neurons produce a small protein, the orexin neuropeptide, known to be involved in promoting wakefulness. Chemotherapy-induced fatigue was reversed when an orexin neuropeptide was given to rodents to counteract the disruption.

Understanding the source of chemotherapy-induced fatigue in cancer patients represents an important turning point in identifying ways to counteract this common debilitating side effect. The results, produced by providing orexin-A neuropeptides to counteract fatigue in rats and mice, suggests that narcolepsy drugs in development, including those in advanced clinical trials, may prove beneficial to cancer patients.

“Our research provides a potential avenue for treatment of chemotherapy-induced fatigue, which undermines the quality of life of many cancer patients,” said Daniel L. Marks, M.D., Ph.D., a lead author on the study. Marks is an investigator with the Knight Cancer Institute and principal investigator and professor of pediatrics in the Papé Family Pediatric Research Institute, OHSU Doernbecher Children’s Hospital. “Understanding the root cause of conditions associated with cancer and its treatment is the goal of personalized cancer medicine and that approach includes taking a holistic view of patient health during cancer treatment and recovery."

The rodent study was conducted with chemotherapy drugs commonly used to treat breast cancer. Up to 90 percent of women receiving chemotherapy for breast cancer experience severe fatigue at some point during or after treatment. Fatigue also puts cancer patients, especially women, at increased risk of bone fracture and cardiovascular disease. Currently, there are no treatments for chemotherapy-induced fatigue. This side effect is managed primarily by instructing patients to spread out their activities to conserve their energy.

Prior to this study, the Marks’ laboratory conducted research demonstrating that fatigue following infection is associated with suppressed orexin-neuron function. Infection and chemotherapy induce a peripheral inflammatory response that is communicated to the brain and likely disrupts neuron function. Orexin neurons are located in the hypothalamus, an area lacking a blood brain barrier. As a result, it is likely susceptible to peripheral insults. Other neurons in the hypothalamus are responsible for signaling responses to illness including stress responses, loss of appetite and fever.

“As a nurse I witnessed the debilitating effects of chemotherapy-induced fatigue and the delay in recovery that resulted,” said Kris Weymann, M.S., R.N., who worked with Marks on the study. “I wanted to better understand the causes of this fatigue, so that we can develop therapies to prevent or manage it and improve functional recovery from cancer.”

Numerous Phase II and Phase III clinical trials are under way that replace or bypass the function of the orexin neuropeptide to treat narcolepsy, a disorder characterized by disrupted wakefulness and impaired orexin neuron signaling. Since chemotherapy was found to disrupt orexin neuron function, further investigation of orexin replacement for chemotherapy-induced fatigue is warranted based on the animal study results.

“A Role for Orexin in Cytotoxic Chemotherapy-Induced Fatigue” was funded by grants from the National Institutes of Health (F31NR01329901,NINR 738 R01NR012479 and NIH R01 DK70333).

In addition to Marks and Weymann, Lisa Wood, Ph.D., R.N., associate professor in the OHSU School of Nursing, and Xinxia Zhu, who holds an M.D. equivalent from China and serves in the Marks Lab at OHSU, contributed to this research.

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