Overcoming Resistance to Anabolic SARM therapy in Experimental Cancer Cachexia with an HDAC Inhibitor

No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hind limb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients. 31 Samples

目前尚无获批用于癌症相关恶病质的治疗方案。结肠癌26癌症恶病质小鼠模型可模拟近期合成代谢抗恶病质疗法在晚期临床研究中的失败结局，且对多种合成代谢剂量的雄激素（包括选择性雄激素受体调节剂（selective androgen receptor modulator，SARM）GTx-024）无应答。组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor，HDACi）AR-42在该模型中展现出抗恶病质活性。本研究探索了SARM与AR-42联合疗法作为优化的抗恶病质治疗范式。低剂量AR-42仅能带来有限的抗恶病质获益，但与GTx-024联合使用时，可较对照组显著提升小鼠体重、后肢肌肉质量及握力。AR-42可抑制肌肉组织中的IL-6/GP130/STAT3信号轴，且不会影响循环细胞因子水平。仅当与AR-42联合使用时，GTx-024介导的β-连环蛋白靶基因调控才可在恶病质小鼠中显现。本研究数据表明，该模型中的恶病质信号通路包含对合成代谢疗法GTx-024不敏感的分解代谢信号，以及可阻断GTx-024介导的合成代谢信号的环节。AR-42可减轻分解代谢基因的激活，并恢复机体对GTx-024的合成代谢应答。将临床已确立的合成代谢疗法GTx-024与处于临床评估阶段的HDACi AR-42联合使用，可为改善恶病质患者的合成代谢应答提供极具前景的策略。本数据集共包含31份样本。