Abstract B266: Systemic inflammation and tissue atrophy in cancer cachexia is mediated by cytokine-dependent protease activation: Physiological and functional improvements through JAK1/2 inhibition

Abstract

Abstract Cancer-associated cachexia (CAC) is a complex syndrome characterized by a detrimental loss of fat and muscle. Approximately 50% of patients suffer from CAC which accounts for a significant proportion of cancer deaths in addition to debilitating constitutional symptoms and poor quality of life. Recently, the Cancer Cachexia Study Group has proposed that systemic inflammation is one of the 3 factors that defines CAC. Consistent with this, we previously demonstrated that inflammatory cytokines are elevated in cachectic mice bearing subcutaneous tumor xenografts. Because many inflammatory cytokines utilize JAK1 and/or JAK2 kinases (JAK1/2) for intracellular signaling, we hypothesized and demonstrated that selective inhibition of JAK1/2 improved tissue preservation and physical performance. Here we extend these studies beyond subcutaneous xenografts and present biochemical data in an effort to better understand the role of JAKs muscle atrophy. Subcutaneous xenograft models are useful tools but may lack host-tumor interactions relevant to CAC. Therefore, we utilized two immune competent models of CAC. Mice inoculated with BaF/3 B-cells transformed with a constitutively active form of JAK2 (JAK2V617F) common in patients with myeloproliferative neoplasms (MPNs) suffer from an aggressive disseminated disease characterized by splenomegaly and weight loss, similar to MPN patients. Compared to normal mice, those inoculated with JAK2V617F expressing cells lost 80% of their fat stores and 15% of skeletal muscle and had severely enlarged spleens (450%). Treatment with an oral selective JAK1/2 inhibitor prevented tissue loss and dramatically reduced spleen size. Similar findings were observed in the ApcMin/+ mouse model of spontaneous colon cancer and CAC. Here, treatment of male mice with a JAK1/2 inhibitor resulted in 120% and 268% increases in fat and muscle stores, respectively. Splenomegaly was also completely eliminated. Importantly, treatment with a JAK1/2 inhibitor markedly improved physical performance as assessed by grip strength and exercise wheel activity (#x003E; 200% of controls). Because JAK activating cytokines are elevated in our models (e.g. IL-6) and have been implicated as causal factors in CAC, we wanted to better understand the impact of aberrant JAK activation on muscle tissue. C2C12 murine myotubes treated with recombinant IL-6 demonstrated increased JAK signaling as measured by elevated levels of pSTAT3 and pSTAT5, canonical substrates of JAK kinases. IL-6 treatment also increased the activity of two intracellular proteases previously linked to muscle catabolism in CAC - cathepsins B and L. Inhibition of JAK1/2 reduced aberrant JAK/STAT signaling in IL-6 treated C2C12 myotubes and in vivo. Moreover, cathepsin activity was decreased explaining, at least in part, the muscle sparing effects of JAK1/2 inhibition observed in vivo. In summary, the data suggest that JAK-activating cytokines are elevated in CAC and contribute to physiological and functional deficits. JAK1/2 inhibition improves signs of inflammation and prevents loss of fat stores and skeletal muscle, the latter, through suppression of cathepsin activity. Clinical exploration of selective JAK inhibition is therefore warranted for the prevention or alleviation of CAC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B266.