Abstract #2848: Small molecule inhibitors of JAK1/2 improve physiological and functional measures of cancer-associated cachexia
Authors: Jordan Fridman, Eian Caulder, Xiaoming Wen, James Rodgers, Andrew Combs, Timothy Burn, Kris Vaddi
Journal: Cancer Research (2009)

Cancer-associated cachexia (CAC) is a significant contributing factor to the morbidity and mortality of malignancy. Though poorly defined, CAC is broadly described as a significant unintended and undesirable weight loss often accompanied by fatigue, altered metabolism, and systemic inflammation. Here, we attempt to understand the role of inflammation in CAC and demonstrate that IL-6, amongst other cytokines, contributes to multiple aspects of cachexia. Furthermore, we show that pharmacological antagonism of inflammatory cytokine signaling - via inhibition of JAK1/2 - reduces aberrant JAK/STAT activity and dramatically improves body mass and physical performance in mouse models of CAC. We characterized CAC using 3 tumor models (Colon26, PC-3M, and A375.S2). Effects of tumors on body weight ranged from total inhibition of weight gain to \#8805;30% weight loss; muscle and fat were depleted with a maximum loss of ~90% of parametrial fat stores and ~50% of gastrocnemius muscle weight. These changes had a dramatic effect on physical performance as demonstrated by decrements in grip strength and locomotor activity approaching 50% and 90%, respectively. Splenomegaly was observed in the majority of models suggesting systemic inflammation may contribute to the cachectic state. We therefore performed an unbiased analysis of plasma samples from cachectic mice and identified a number of markedly elevated inflammatory cytokines and chemokines, many of which signal through the non-receptor tyrosine kinases JAK1/2 (e.g. IL-6, IL12, and IL17) or which are indirectly stimulated by such cytokines (e.g. IL-6 induced MCP-1). Moreover, administration physiological relevant levels of IL-6 was sufficient to activate JAK/STAT in muscle and result in reduced lean body mass and grip strength. Because of the reported and observed inflammatory components of CAC, we hypothesized that pharmacological inhibition of JAK1/2 may prevent or improve the cachectic phenotype. Using selective inhibitors (INCB16562 and INCB19408), we demonstrated that systemic inhibition of JAK1/2 reduces aberrant JAK/STAT signaling in muscle in the aforementioned models, minimizes splenomegaly and has a marked tissue salvaging effect on both fat and muscle resulting in striking functional improvements (~200%) in strength and activity. These effects were not associated with changes in food consumption or tumor growth. In summary, the data suggest that multiple JAK-activating cytokines are elevated in CAC and contribute to functional deficits associated with the condition. Moreover, we show that systemic inhibition of JAK1/2 can reduce inflammation, improve total and lean body mass, and enhance functional performance in multiple cachexia models. Clinical exploration of selective JAK inhibition is therefore warranted for the prevention or alleviation of CAC.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2848.