Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY Cachexia affects over 50% of individuals with cancer and is characterized by severe skeletal muscle wasting and poor muscle function. This wasting of lean mass is known to be strongly correlated to mortality and poor tolerance to common chemotherapeutic treatments. Lung cancer is not only the second most prevalent cancer worldwide but is also known to lead to severe cachexia. Targeting lung cancer cachexia would substantially improve the quality of life for patients with cancer. Recently, a lipid-specific form of reactive oxygen species known as lipid hydroperoxides (LOOH) have been linked to skeletal muscle atrophy as a result of age, disuse, and denervation. My preliminary findings suggest LOOH is elevated in the skeletal muscle of various lung tumor bearing mouse models. In vitro, genetic, and pharmacologic suppression of LOOH or their reactive lipid aldehydes prevented myotube atrophy induced by co-culture with Lewis Lung Carcinoma (LLC) cells. Based on these observations, I propose elevated LOOH plays a significant role in the development of the cachexia phenotype. I will now interrogate this potential mechanism in vivo by measuring skeletal muscle mass and function in LLC xenograft and genetic lung cancer models with or without genetic or pharmacological suppression of LOOH. I will meet regularly with my mentoring team of muscle biology and lung cancer experts who will support my research training into the molecular mechanisms of muscle atrophy with cachexia. Additionally, our collaboration with the Huntsman Cancer Institute at University of Utah provides a strong platform for utilization of xenograft and genetic mouse models of lung cancer to interrogate this potential mechanism. This proposal aims to address a severe condition affecting those with lung cancer and our hope is these findings will provide a foundation for future work to target lung cancer cachexia therapeutically.
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