Cancer Cachexia

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Cancer is one example where a small cellular change can alter metabolism so greatly that the body loses its ability to maintain essential nutrients like triglyceride and amino acids. This cachexia syndrome causes patients to waste away and die of frailty and immobility. It has no clear diagnostic methodology, no known mechanism, and no FDA-approved treatment.
— Marcus G.
 

1. Ketones

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In preliminary experiments using an inducible, genetically engineered mouse model of non-small cell lung cancer (NSCLC), we have identified the loss of hepatic PPARα-dependent ketone production as an important feature of cachexia. Restoring ketone production using the PPARα agonist, fenofibrate, prevents the loss of skeletal muscle mass and body weight. At this time, it is unclear whether the protection of muscle mass is due to the fenofibrate-induced replacement of serum ketones, directly.  In this project we are treating tumor bearing mice with different dietary strategies that modulate serum ketone levels to test the effects on skeletal muscle mass and metabolism.

 

2. Glucocorticoids

Braun and Marks, The regulation of muscle mass by endogenous glucocorticoids. Front. Physiol., 03 February 2015

Braun and Marks, The regulation of muscle mass by endogenous glucocorticoids. Front. Physiol., 03 February 2015

The putative role of glucocorticoid signaling in cachexia remains unclear due to the use of inappropriately aggressive cancer models and non-specific techniques to modulate the hypothalamic-pituitary-adrenal (HPA) axis, such as adrenalectomy.  In other catabolic states (e.g., fasting), glucocorticoids play an essential role in regulating systemic and skeletal muscle metabolism.  In skeletal muscle, elevated glucocorticoids coordinate the breakdown of structural proteins, the inhibition of protein synthesis, and the metabolic switch to more efficient fuel sources, such as fatty acids. In this project we are testing the hypothesis that glucocorticoids directly result in the skeletal muscle destruction observed in NSCLC-associated cachexia by using chemical inhibitors of the HPA axis and genetic models that do not respond to glucocorticoids.

 

3. Tumor Signals

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Despite mice being highly inbred, only 60% of mice with NSCLC develop cachexia.  This finding suggests that additional genetic mutations or epigenetic changes arise in the tumors over time and lead to cachexia development. We hypothesize that a tumor-released factor reduces PPARα activity in the liver, which leads to loss of body weight and skeletal muscle in cachexia mice.  This “cachexia-inducing factor” has yet to be identified and characterized from endogenous lung tumors.  We are using a variety of unbiased "-omics" based strategies to (1) identify unique messages and proteins that are associated with cachexia, and (2) validating these hits using cell culture and genetic mouse models.

 

4. Adiponectin

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Adiponectin is an adipocyte-derived hormone that enhances fatty acid oxidation in the liver and skeletal muscle. Given our early findings in mice with cachexia, we believe adiponectin therapy may be a useful therapeutic strategy to prevent muscle wasting. This hypothesis will be tested using genetically engineered mice and viral expression vectors.

 

5. Skeletal Muscle Metabolism

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Skeletal muscle mitochondrial dysfunction has been reported with cachexia in cancer patients and preclinical models. Our lab is interested in understanding the changes that occur in glycogen metabolism, glycolysis, and oxidative phosphorylation as cachexia develops.