Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia

Summary Chemotherapy is a mainstream treatment for most cancers, despite recent progress in the development of new therapies for cancer. A well-documented long lasting toxicity of some chemotherapy agents is their capacity to cause or intensify muscle wasting and fatigue in cancer patients, which are manifestations of cachexia. Cachexia is a metabolic disorder contributing significantly to cancer-related morbidity and mortality due to systemic wasting, as well as decreasing the efficacy while increasing the toxicity of chemotherapy. Consequently, patients suffering from chemotherapy-related muscle wasting may experience difficulty adhering to or completing treatment regimens and may require delays in treatment, dose limitation, or discontinuation of therapy. Further, chemotherapy-related muscle wasting and fatigue can persist for months to years after the cessation of chemotherapy. Thus, the interplay between chemotherapy and cachexia is a significant threat to cancer patient survival and quality of life. However, the underlying mechanism of the detrimental effects of chemotherapy on skeletal muscle is poorly understood, and there is no FDA-approved treatment for this chemotherapy toxicity. The current proposal aims to address this clinical paradox by testing a novel hypothesis for the mechanism through which fluorouracil (5-FU) and cisplatin, two widely prescribed chemotherapy agents, promote cancer’s capacity to induce muscle wasting in tumor-bearing mice. Previously, supratherapeutic doses of 5-FU were shown to promote muscle dysfunction directly in cancer-free animals by causing mitochondrial dysfunction and oxidative stress but not activating the ubiquitin-proteasome pathway that mediates muscle protein loss. Given that 5-FU is used in cancer patients, it is necessary to understand whether and how 5-FU promotes muscle wasting at therapeutically relevant doses in cancer hosts. Similarly, cisplatin has been shown to cause muscle dysfunction directly in cancer-free mice at a supratherapeutic dose, but whether and how it promotes muscle wasting in cancer hosts are undefined. These knowledge gaps prevent clinical intervention of chemotherapy- associated cachexia. Based on preliminary data, the current project is designed to test the hypothesis that 5- FU and cisplatin cause or intensify muscle wasting in cancer hosts indirectly by stimulating the intrinsic capacity of cancer cells to induce muscle protein degradation at therapeutic doses, and to elucidate the underlying mechanisms of this action. Leveraging these findings, experimental therapies will be carried out by repurposing existing pharmacological agents that inhibit 5-FU and cisplatin’s capacity to stimulate cancer-induced muscle wasting. If successful, these drugs can be quickly tested in clinical settings for intervention of chemotherapy- associated muscle wasting.