PROJECT SUMMARY Cachexia is a multi-factorial syndrome accompanying cancer, with the most notable symptom being unintentional weight loss due to a depletion of skeletal muscle and adipose tissue mass. Cachexia affects approximately 50% of all cancer patients, and nearly all patients with advanced disease. While it is difficult to quantify the number of patient deaths that result directly from cachexia, it is clear that cancer cachexia is a significant contributor to negative outcomes of cancer patients. This is particularly true for patients with gastrointestinal cancers, such as pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma patients have both the highest incidence and severity of disease-associated weight loss. Published data, including our own, have consistently shown that male and female PDAC patients have similar incidence and severity of cachexia. However, our preliminary data suggest that while relative weight loss may be equivalent between males and females, there is a striking difference between these two groups. While cachectic males appear to lose skeletal muscle mass in proportion to their total body weight losses, cachectic females may instead lose weight primarily due to adipose tissue loss. Furthermore, we hypothesize that males and females respond differently to anti-cachexia treatment, including ghrelin receptor antagonization. This proposal seeks to test our hypothesis of a sexual dimorphism in cancer cachexia and response to anti-cachexia treatment using a combination of retrospective clinical analyses and mouse modeling. Completing the proposed research will have a significant impact on our understanding of sexual dimorphisms in cancer cachexia and response to anti-cachexia treatment. If our hypothesis is correct, our findings would alter how anti-cachexia clinical trials are designed and how future therapeutics are used clinically.

PROJECT NARRATIVE The severe weight loss of pancreatic cancer-induced cachexia due to muscle and adipose tissue wasting is a significant contributor to patient morbidity and mortality. This application seeks to understand if the body composition changes of cachexia differ between male and females and if males and females respond differently to anti-cachexia treatment. We expect our findings to have lasting impacts on the design of future anti-cachexia clinical trials and therapeutic strategies.