Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
Nat Commun. 2022 Aug 8;13(1):4633. doi: 10.1038/s41467-022-32135-0.
Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.
癌症恶病质是一种常见的、使人虚弱的病症，目前治疗方法有限。我们利用已建立的肺癌小鼠模型发现恶病质的特征是食物摄入量、自发性活动和能量消耗减少，同时伴有肌肉代谢功能障碍和萎缩。我们确定激活素 A 是恶病质的一个潜在驱动因素，并使用 ActRIIB-Fc（TGF-β/激活素家族成员的诱饵配体）和 anamorelin（Ana，一种胃饥饿素受体激动剂）分别治疗，以分别逆转肌肉功能障碍和厌食症。Ana 可有效增加食物摄入量，但只有药物联合使用才能增加瘦体重、恢复自发性活动并提高整体存活率。这些有益效果仅限于雌性小鼠，且依赖于卵巢功能。同样，在人类肺腺癌中高表达的 Activin A 仅与女性患者的不良预后相关，尽管在两性中表达水平相似。这项研究表明，需要采用多模式、性别特异性疗法来逆转恶病质。
