Abstract 5435: Beta-3 adrenergic antagonism can alleviate energy wasting associated with cancer-induced cachexia

Abstract

Abstract Introduction: Cancer-associated cachexia (CAC) is a wasting syndrome characterized by atrophy of adipose tissue and skeletal muscle as a consequence of cancer. CAC has been shown to be responsible for approximately 20% of cancer deaths alone and reduces tolerance to treatment. The pathological mechanisms underlying this syndrome remains elusive and the treatment options are scarce. One proposed mechanism is the tumor-induced activation of brown adipose tissue (BAT); a thermogenic organ that wastes energy by producing heat via activation of uncoupling protein 1 (UCP1). β3 adrenergic signaling is a strong activator of BAT and the browning of white adipose tissue (WAT). We hypothesized that treatment with a specific β3 antagonist could alleviate CAC. Method: To study cachexia, the LuCAP 32 xenograft model of human prostate cancer was utilized in immunodeficient balb/ca nude mice. After two weeks of tumor growth, treatment with the specific β3 antagonist SR59230A (SR) was started using subcutaneous micro osmotic pumps. Vehicle substance and nontumor bearing (NTB) mice were used as controls. The mice were sacrificed after a treatment period of four weeks and tissues were harvested for subsequent analysis. The PCR analysis was normalized to NTB mice. Results: The mice with tumor started losing weight 20 days after tumor implantation while the nontumor bearing controls gained weight throughout the experiment. The group treated with SR also lost weight but to a significantly lesser degree than vehicle treated animals (-1.7 vs -3.2 g, p=0.032). This was also seen when looking at individual fat depots. Whole body composition, measured by echo MRI, showed that all groups equally lost fat mass over time. However, lean mass in the vehicle group decreased whereas the SR group gained lean mass (-0.41 vs 1.18 g, p=0.036). With respect to total body weight this gain in lean mass was counteracted by the loss of fat mass. PCR analysis of subcutaneous WAT showed a significant decrease in expression of ATGL (2.84 vs 1.98 FC, p=0,006), PPARγ (2.33 vs 1.45 FC, p=0.026) and CD36 (2.11 vs 1.3 FC, p=0.008) for the SR group compared to vehicle, indicating a decreased lipolysis and influx of fatty acids to WAT. The SR treated mice also had a significantly lower expression of UCP1 in WAT compared to controls (2.23 vs 0.58 FC, p=0.023), supporting the notion that the browning of WAT is a driving force for CAC. Conclusion: Our data show that treatment with a specific β3 adrenergic antagonist alleviates CAC through decreased lipolysis of WAT and decreases the expression of markers for WAT browning. This indicates a correlation between decreased browning and severity of CAC. We also provide evidence that β3 antagonism helps preserve muscle mass, which is of major importance for treatment of CAC and something that few other treatment options have been able to show. Citation Format: Fredrick Anderson, Stefan K. Nilsson, Jonas A. Nilsson. Beta-3 adrenergic antagonism can alleviate energy wasting associated with cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5435. doi:10.1158/1538-7445.AM2017-5435