Targeting circulating HSP70 and HSP90 for the treatment of cancer cachexia

摘要 恶病质，以肌肉萎缩为特征，是癌症的一种致命并发症，在超过50%的 癌症患者和癌症相关死亡的直接原因约占30%。然而，由于穷人的原因 由于对其高度复杂的病因的了解，目前还没有FDA批准的癌症恶病质的治疗方法。 我们最近在小鼠癌症模型中发现，癌细胞释放循环中的HSP70和HSP90 与外体类型相关的胞外小泡(EV)是通过激活而导致肌肉萎缩的关键诱因 TLR4在骨骼肌细胞上的表达。此外，循环中升高的HSP70/90是导致血管紧张素转换酶升高的原因 这种分解代谢的细胞因子，如TNFa和IL-6，是由于它们全身激活TLR4所致。这些数据表明 循环HSP70/90升高是炎症和肌肉萎缩的关键诱因，而炎症和肌肉萎缩是主要的 癌症恶病质的特征。因此，靶向癌细胞释放的EV相关HSP70和HSP90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，进一步验证其作用将是重要的 在人类癌症恶病质中循环HSP70和HSP90升高的情况，这是由于缺乏工具来阻止 截获人体内循环中的HSP70和HSP90。在这个R21应用程序中，我们建议检验假设 循环HSP70和HSP90升高是人类癌症恶病质肌肉萎缩的关键诱因 产生抗人HSP70和HSP90的中和抗体，具有高效、特异和 确定表位，并确定抗体在体外和体内是否改善肌肉萎缩 人类癌症恶病质模型。如果成功，这些抗体可以用于未来的临床研究 确定阻断升高的循环HSP70和HSP90是否可以改善癌症患者的肌肉萎缩 病人。

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.