Effects of Riluzole on CNS Glutamate and Fatigue in Breast Cancer Survivors With High Inflammation

Fatigue, Inflammation

Central Nervous System (CNS) Glutamate, Breast Cancer Treatment, Fatigue, Cognitive Dysfunction, Behavioral, Psychometrics, Imaging Technology, Magnetic Resonance Spectroscopy

The goal of the proposed research is to determine whether riluzole, a drug that increases glutamate reuptake, will decrease central nervous system (CNS) glutamate in breast cancer survivors with increased inflammation and fatigue. The researchers will also determine whether decreasing glutamate with riluzole will reverse inflammation-related fatigue and other symptoms including cognitive dysfunction and decreased motivation. To accomplish these goals, the researchers plan to conduct an 8 week, double-blind, randomized control trial of riluzole (100 mg/d) versus placebo in 40 breast cancer survivors (n=20 per group). All breast cancer survivors will have completed treatment within 1-3 years and have a fatigue level of ≥4 (on a 10 point scale) and a plasma c-reactive protein (CRP) concentration \>3mg/L (indicative of high inflammation). Participants will undergo magnetic resonance spectroscopy (MRS) to measure CNS glutamate before and after 2 and 8 weeks of riluzole or placebo treatment. Fatigue and other behavioral assessments including measures of cognitive function and motivation will be conducted before and after treatment and correlated with the change in CNS glutamate.

Breast cancer is one of the most common cancers among women with \ 250,000 new cases diagnosed in the US each year. Significant advances have been made in treating breast cancer, and the current number of women in the US who are considered breast cancer survivors is over 2 million. Despite these advances, breast cancer and its treatment comes at a considerable cost for a significant percentage of women with up to 30% of women experiencing behavioral and/or cognitive symptoms months to years after treatment completion. The mechanisms which contribute to these symptoms are only beginning to be understood, however, mounting data suggest that inflammation may be involved. Prior research has demonstrated significant relationships between inflammatory markers and inflammatory signaling pathways and symptoms of fatigue and cognitive dysfunction in patients with multiple forms of cancer including breast cancer. There are a number of theories as to how inflammation may influence fatigue and cognition function in breast cancer patients. One neurotransmitter pathway that may be involved is glutamate. Inflammatory cytokines have been shown to decrease glutamate reuptake and increase glutamate release from astrocytes. The primary objective of this study is to provide the first data on the role of CNS glutamate and symptoms of fatigue in breast cancer patients using MRS and a medication that has been shown to lower CNS glutamate in animal models and human subjects. No previous study has examined the potential connection between increased inflammation, increased CNS glutamate and symptoms in breast cancer patients, although there is strong clinical and preclinical support for an important interrelationship among these variables. Identification of a significant relationship between increased CNS glutamate and symptoms will: * Enable the development of inflammatory biomarkers to identify patients with altered CNS glutamate. * Help focus future studies using glutamate stabilizing medications and glutamate antagonists on patients most likely to respond to glutamate-targeted therapies (personalization of trials and treatment). * Expand treatment studies to include synergistic or sequential targeting of inflammation and glutamate to reduce symptom burden in breast cancer patients. This study will also serve as a foundation for efforts to link the impact of inflammatory cytokines and their relationship with increased CNS glutamate and behavior to a variety of cancers. Moreover, by testing novel treatment approaches (targeting glutamate), this study may ultimately improve the quality of life of breast cancer and other cancer patients.

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