Schneider, Jessica Z.

Cancer cachexia is a multifactorial syndrome involving muscle and fat wasting, inflammation, and metabolic dysfunction. Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at ∼80%. Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice. We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by α-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.

Abstract Cancer cachexia is a multifactorial syndrome entailing muscle and fat wasting, inflammation, and metabolic dysfunction. Pancreatic cancer has the highest incidence of cachexia at around 80%. However, there are no FDA approved therapy for cachexia in the clinic yet. This is mostly because of the failure of preclinical therapies to demonstrate success in the clinic. Most preclinical studies utilize 6-8 week old mice which roughly corresponds to a human age of ~ 20 years. However, the median age of diagnosis of pancreatic cancer is ~70 years. Given widespread physiology, microenvironment, and metabolism differences in young and aged skeletal muscle, we sought to study cancer cachexia in mice aged to >78 weeks, which corresponds to a human age of greater than 60 years. Our previously published study reported little difference in tumor growth or survival between the two cohorts, yet significant alterations in the muscle transcriptome. Building on this work, we show significant differences in the muscle metabolome of young/aged control and tumor bearing mice. Notably, histamine was higher in aged versus young control mice and even higher in the aged tumor-bearing cohort. We show higher activity of histamine decarboxylase (HDC), the enzyme that converts histidine to histamine in the muscles of aged tumor-bearing mice. Addition of cancer conditioned-media (CM) to C2C12 myotubes was able to induce histamine production and HDC activity in vitro, which demonstrates the ability of muscle cells to induce histamine independent of mast cells. We further show that addition of histamine to myotubes is sufficient to increase atrophy-associated markers. Inhibition of HDC activity by α-fluoromethylhistidine (FMH) in the in vitro model of cachexia protected against myotube thinning. Finally, we treated tumor-bearing aged mice with FMH and observed a) decreased histamine in the muscles 2) decreased HDC activity in the muscles 3) decreased muscle wasting, 4) decreased atrophy markers. Together, we present a novel wasting-associated metabolic pathway and corresponding therapeutic avenue for cancer cachexia that may have been overlooked if not for the use of a more-age-appropriate model of pancreatic cancer. Citation Format: Aneesha Dasgupta, Rebecca E. Schmitt, Jessica Z. Schneider, Tatsuyoshi Kono, Chih-Chun Lee, Carmella Evans-Molina, Jason D. Doles. Targeting differential metabolism in an aged model of cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 356.