Modeling muscle wasting in cancer cachexia

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Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. This syndrome occurs in a majority of cancers and contributes to approximately one third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder, and disappointing results from recent Phase III clinical trials indicate that a cachexia treatment is not likely to appear soon. A potential contributing factor to the lack of progress in the clinic may be linked to the current models that a majority of laboratories in the cancer cachexia field are using in their pre-clinical studies. The most common of these models utilize mice where xenograft tumors induce muscle loss on an accelerated time scale with a large tumor load that is not reflective of conditions experienced by cachectic cancer patients. New efforts have been launched to produce models that better recapitulate those cancers with a high incidence of muscle loss, such as pancreatic cancer. One such model called KPC is a genetically engineered mouse that develops pancreatic cancer and was recently described to exhibit a cachectic phenotype. Our laboratory pursued investigations with the KPC mouse in hopes of discovering new mechanisms of muscle wasting. However, data we have accumulated suggest that the KPC mouse is not a true model of cachexia. With our goal to faithfully recapitulate the cachexia phenotype seen in pancreatic cancer patients, we developed an alternative genetic mouse model, which significantly, shows a strong correlation between muscle loss and tumor progression. We hypothesize that this new mouse model shares common mechanisms of cancer-induced muscle wasting with pancreatic cancer patients and will be useful for translational studies and targeted therapeutics. To test this hypothesis we will validate the model by 1) identifying markers that are comparable to cachexia in the human disease; and 2) performing a pre-clinical trial to determine the efficacy of inhibiting the myostatin/activin pathway. Achieving our goal to generate a bona fide mouse model of cancer cachexia will accelerate our understanding of the underlying causes of muscle wasting, which should translate to improving the current pipeline of anti-cachexia therapies.