Targeting circulating HSP70 and HSP90 for the treatment of cancer cachexia

总结 恶病质是一种致命的癌症并发症，其特征是肌肉萎缩， 癌症患者和~30%癌症相关死亡的直接原因。然而，由于穷人 尽管对癌症恶病质的病因学高度复杂，但FDA尚未批准用于癌症恶病质的治疗。 我们最近在小鼠癌症模型中发现，癌细胞释放的循环HSP 70和HSP 90 与外泌体型细胞外囊泡（EV）相关的蛋白质是肌肉萎缩的关键诱导物， TLR 4对骨骼肌细胞的作用。此外，升高的循环HSP 70/90负责升高 这些分解代谢细胞因子如TNF α和IL-6由于它们对TLR 4的系统性激活而被激活。这些数据表明 升高的循环HSP 70/90是炎症和肌肉萎缩的关键诱导物，这是主要的 癌症恶病质的特征。因此，靶向癌细胞释放的EV相关HSP 70和HSP 90可能是 癌症恶病质的有效治疗策略。然而，动物模型并不总是概括 在人类癌症恶病质中发生的复杂事件，重要的是要向前迈进，以验证角色 在人类癌症恶病质中，循环HSP 70和HSP 90升高，这是由于缺乏工具， 在人体内拦截循环HSP 70和HSP 90。在这个R21应用程序中，我们建议测试假设 升高的循环HSP 70和HSP 90是人类癌症恶病质中肌肉萎缩的关键诱导物， 产生具有高效力、特异性的针对人HSP 70和HSP 90的中和抗体， 确定的表位，并确定抗体是否在体外和体内改善肌肉萎缩 人类癌症恶病质的模型。如果成功，这些抗体可用于未来的临床研究， 确定阻断升高的循环HSP 70和HSP 90是否能改善癌症中的肌肉萎缩 患者

Summary Cachexia, characterized by muscle wasting, is a lethal complication of cancer seen in more than 50% of cancer patients and the immediate cause of ~30% cancer related death. However, due to the poor understanding of its highly complex etiology, there has been no FDA-approved treatment for cancer cachexia. We recently discovered in mouse cancer models that cancer cell-released circulating HSP70 and HSP90 associated with exosome-type extracellular vesicles (EV) are key inducers of muscle wasting by activating TLR4 on skeletal muscle cells. In addition, elevated circulating HSP70/90 are responsible for the elevation of such catabolic cytokines as TNFa and IL-6 due to their systemic activation of TLR4. These data suggest that elevated circulating HSP70/90 are key inducers of inflammation and muscle wasting, which are the primary features of cancer cachexia. Thus, targeting cancer cell-released EV-associated HSP70 and HSP90 could be an effective therapeutic strategy for cancer cachexia. However, animal models do not always recapitulate complex events that occur in cancer cachexia in humans, it will be important moving forward to verify the roles of elevated circulating HSP70 and HSP90 in human cancer cachexia, which is hindered by the lack of tools to intercept circulating HSP70 and HSP90 in humans. In this R21 application, we propose to test the hypothesis that elevated circulating HSP70 and HSP90 are key inducers of muscle wasting in human cancer cachexia by generating neutralizing antibodies against human HSP70 and HSP90 with high efficacy, specificity, and defined epitopes, and determining whether the antibodies ameliorate muscle wasting in in vitro and in vivo models of human cancer cachexia. If successful, these antibodies can be used in future clinical studies to determine whether intercepting elevated circulating HSP70 and HSP90 ameliorates muscle wasting in cancer patients.