Abstract 2680: Inhibition of activin-like kinases 4 and 5 attenuates cancer cachexia associated muscle wasting

Background: Cancer cachexia has a detrimental effect on patient survival. Cachectic patients experience reduced quality of life and have a decreased survival time. The underlying mechanism behind cancer cachexia is not yet fully understood. Recent experimental data suggests myostatin signaling may be a key contributor in the pathogenesis of cancer cachexia. Activin receptor IIB / activin-like kinase 4/5 heterodimer activation by myostatin leads to catabolic muscle degradation. SB-431542 is a potent inhibitor of activin-like kinases 4 and 5. We aimed to assess its potential in the treatment of cancer cachexia in an experimental rodent model. Methods: All experiments were approved by the local Animal Ethics Committee. 24 CD2F1 were inoculated subcutaneously with 0.5 x 106 colon-26 murine adenocarcinoma cells to induce cachexia. The mice were allocated randomly into one of four experimental groups: healthy control, tumor-bearing control, tumor-bearing vehicle treated and tumor-bearing SB-431542 treated. All mice were weighed daily. Tumor size was assessed every other day, starting day 9 post inoculation. Four-paw grip strength was determined weekly using a grip-strength meter. SB-431542 was reconstituted in DMSO 1 mg/mL. From day 5 post inoculation, allocated mice received 10 mg/kg SB-431542, or vehicle intraperitoneally until sacrifice on day 20. Results: All tumor-bearing mice had a reduction in body weight compared to controls, 21.1 ± 2.1 g versus 30.0 ± 1.3 g respectively (p < 0.0001). No differences in body weight were found between the tumor-bearing groups. Despite weight loss, SB-431542 treated animals had no reduction in grip strength. Grip strength directly after tumor inoculation was 200.9 ± 11.3 g, and on day 14 211.3 ± 20.4 g. Vehicle treated animals showed a reduction from 204.0 ± 19.1 g to 174.8 ± 13.7 g (p = 0.0158). Mean wet muscle weight of the m. tibialis anterior was significantly preserved in SB-431542 treated animals versus tumor-bearing vehicle treated animals (53.8 mg vs. 40.5 mg, p = 0.0171) as well as tumor-bearing untreated animals (53.8 mg vs. 34.7 mg, p = 0.0002). Conclusion: These findings suggest that inhibition of activin-like kinases 4 and 5 by SB-431542 attenuates cancer cachexia associated muscle loss and loss of muscle force in experimental cancer cachexia, and further emphasizes the role of myostatin/activin signaling. Citation Format: Stef Levolger, Ron W.F. de Bruin, Jan N.M. IJzermans. Inhibition of activin-like kinases