Training and Research on Mechanisms of Pancreatic Cancer Associated Muscle Wasting and Related Therapies

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Abstract Skeletal muscle wasting (SMW) is a growing burden among cancer survivors and is prognostic of treatment failure, radiotherapy toxicity, and a shorter time to tumor progression related to survival. This is of particular concern for patients with pancreatic ductal adenocarcinoma (PDAC), for whom interventions for severe SMW are now being implemented prior to surgery, radiation and chemotherapy, so that these patients can complete their prescribe treatments. Currently, the mechanism(s) that lead to cancer-related SMW have yet to be elucidated. Furthermore, viable treatment options for patients with this multifactorial syndrome remain undiscovered. A lack of preclinical models that recapitulate human disease is often identified as an obstacle in the development of feasible therapies to treat cancer-related SMW. To this end, our lab developed a murine model of PDAC-related SMW that parallels human pathology and can be longitudinally assessed via Dual Energy X-ray Absorptiometry (DEXA). In this murine model of PDAC we have identified upregulation of pro-inflammatory cytokines, immune cell infiltration, IGFBP-3, and intramuscular adipogenesis as key features in the progression of SMW. In addition, we determined that a single intratumoral injection of IL-12 reduced tumor burden, pro-inflammatory signaling, and SMW, while improving survival out to 50 days. Although a relationship between chronic low grade inflammation and PDAC-related SMW has been suggested, the mechanisms are unknown. Also, the relationship betwe en macrophage associated increases in IGFBP-3 and adipogenesis have yet to be investigated. Thus, the purpose of this proposal is to investigate a novel pathway of SMW and increased intramuscular adipogenesis via pathologic increases in IGFBP-3 by tumor and immune cells. In addition, we seek to determine the efficacy of a multi-dose IL-12 treatment regimen to ameliorate SMW through the reduction of inflammation, intramuscular macrophage infiltration, IGFBP-3 secretion, and adipogenesis in a murine model of PDAC.