Abstract
Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is an aggressive gastrointestinal cancer, with a fiveyear survival rate of less than 5%[1]
We show that neither genetic deletion of TLR9 nor blockade of Toll-like receptor 7 and 9 (TLR7/9) using IRS 954 significantly altered the metabolic changes associated with pancreatic cancer cachexia
To our knowledge this is the first study to investigate the efficacy of Toll-like receptors (TLRs) blockade for the treatment of cachexia in PDA, we and others have previously shown that TLRs play an important role in the pathogenesis of pancreatic cancer[49]
Summary
Pancreatic ductal adenocarcinoma (PDA) is an aggressive gastrointestinal cancer, with a fiveyear survival rate of less than 5%[1]. Mortality and poor quality of life in these patients is related to the significant metabolic and nutritional derangements associated with the cancer cachexia syndrome. This syndrome is present in up to 80% of PDA patients and accounts for up to 22% of all cancer-related deaths[4,5,6]. Neurocognitive effects of cachexia include fatigue, impaired memory and cognition, and decreased physical activity secondary to increased resting energy expenditure[8, 9] These derangements reduce the quality of life in cachectic patients and may even contribute to a decreased therapeutic response to chemotherapy[10]
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