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.