Abstract 3458: Investigation of oxidative stress-related gene signature in cancer-associated cachexia

Abstract

Abstract About eighty percent of pancreatic cancer patients demonstrate excessive loss of skeletal muscles with or without loss of adipose deposits, a condition known as cancer-associated cachexia. Severe complexities related to cancer-associated cachexia contribute to mortality in one-third of pancreatic cancer patients. Multiple factors, including loss of appetite, systemic inflammation, digestive enzymes, and hormonal imbalance may contribute to the development of cancer-associated cachexia. Poor understanding of the molecular mechanism is the key challenge for targeting cancer-associated cachexia. Hence, to facilitate the identification of new targets for ameliorating cancer-induced muscle loss, we undertook genomic studies. We evaluated differentially expressed gene signatures in muscle tissues of cachectic and non-cachectic human pancreatic cancer patients. To better model the mechanisms of cancer cachexia, we also compared the identified gene signatures to that of orthotopic and spontaneous mice models of pancreatic cancer cachexia. We observed significant alterations in multiple genes related to oxidative stress in muscle tissues from human patients with cachexia and mice cachexia models. We targeted oxidative stress regulatory genes by genetic manipulations or targeted oxidative stress with pharmacological approaches to evaluate the impact of oxidative stress in skeletal muscles on cancer-associated cachexia. Our results suggest that targeting the oxidative stress pathway prevents/reverts cancer-associated cachexia. Moreover, inhibition of oxidative stress also abolished cancer cell-conditioned medium-induced atrophy in C2C12-derived myotubes and diminished the expression of atrophy markers. Overall, our studies revealed the potential role of oxidative stress induced by cancer cells in muscle wasting. Future studies to target tumor-induced oxidative stress in muscle fibers may provide new therapeutic approaches to prevent cancer-associated cachexia. Citation Format: Sumeet Jain, Surendra K. Shukla, Aneesha Dasgupta, Pankaj K. Singh. Investigation of oxidative stress-related gene signature in cancer-associated cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3458.