Abstract 4090: Generation of a new mouse to model pancreatic cancer-induced cachexia

Abstract

Abstract Of all cancers, pancreatic cancer causes the third most fatalities, and incidence rates of this devastating disease continue to rise. Further, pancreatic cancer presents with the highest incidence of cachexia, a syndrome of weight loss due to depletion of skeletal muscle and adipose tissue. Clinically, cachexia is associated with increased mortality, poor quality of life, poor treatment responses, and increased treatment complications. Although clearly the best way to prevent cachexia is to address the cancer, pancreatic cancer has proven challenging to treat, with a dismal 9% 5-year survival rate. We believe effective anti-cachexia therapy will improve the care of pancreatic cancer patients, but the development of these therapies will require animal models that accurately recapitulate the etiology of pancreatic cancer-induced cachexia. To improve on the current, non-pancreas tumor xenograft models of cachexia, we generated a genetically engineered mouse model (GEMM) of pancreatic cancer, where induction of Kras and loss of the tumor suppressor Pten occurs in the pancreas of postnatal mice, which we refer to as the KPP model. KPP mice progressively lose skeletal muscle and adipose mass as a result of their cancer. We find that KPP mice exhibit histologic features of pancreatic ductal adenocarcinoma and reach endpoint criteria at an average of 107 days of age. Beginning at approximately 75 days of age, KPP mice undergo progressive loss of existing skeletal muscle mass, resulting in decreased muscle function. We also find that muscle loss from KPP mice exhibits a gene expression signature that closely aligns with the gene expression signature in muscle from cachectic pancreatic cancer patients. In summary, we expect KPP mice to serve as a useful model to elucidate the underlying mechanisms of muscle loss in pancreatic cancer-induced cachexia and to evaluate potential anti-cachexia therapies. Citation Format: Erin E. Talbert, Katherine J. Ladner, Maria Cecilia Cuitino, Gustavo W. Leone, Denis C. Guttridge. Generation of a new mouse to model pancreatic cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4090.