Targeting circulating HSP70 and HSP90 for the treatment of cancer cachexia

靶向循环 HSP70 和 HSP90 治疗癌症恶病质

基本信息

批准号：
10212970
负责人：
YI-PING LI
金额：
$ 16.65万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-08 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212970
关键词：
Animal Model Antibodies Autophagocytosis Bispecific Antibodies Blood Circulation Cachexia Cancer Model Cancer Patient Cancer cell line Cell membrane Cessation of life Clinical Research Collaborations Complex Consumption Data Engineering Epitopes Etiology Event Exposure to FDA approved Future Genes Heat-Shock Proteins 70 Heat-Shock Proteins 90 Human In Vitro Inflammation Institution Intercept Interleukin-6 Lewis Lung Carcinoma Lysosomes MAP Kinase Gene Malignant Neoplasms Membrane Proteins Metabolic syndrome Monoclonal Antibodies Multivesicular Body Mus Muscle Cells Muscle Fibers Muscular Atrophy Oranges Pathway interactions Role Source Specificity Surface TLR4 gene Testing Therapeutic antibodies Ubiquitin Xenograft procedure antibody engineering base cancer cachexia cancer cell cancer complication cancer therapy chemotherapy cytokine exosome extracellular vesicles factor C human model in vivo in vivo Model multicatalytic endopeptidase complex neoplastic cell neutralizing antibody pancreatic cancer cells preclinical study prevent therapeutically effective tool transcription factor tumor

项目摘要

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.

概括病原体以肌肉浪费为特征，是超过50％的癌症的致命并发症癌症患者和癌症与癌症有关的直接原因与癌症有关的直接死亡。但是，由于贫穷对其高度复杂的病因的理解，没有FDA批准的癌症恶病质治疗方法。我们最近在小鼠癌模型中发现了癌细胞发行的循环HSP70和HSP90 与外泌体型细胞外囊泡（EV）相关的是肌肉浪费的关键诱导者 TLR4在骨骼肌细胞上。此外，高架循环HSP70/90负责高程由于TLR4的全身激活TNFA和IL-6等分解代谢细胞因子。这些数据表明循环HSP70/90升高是炎症和肌肉浪费的关键诱导剂，这是主要的癌症恶病质的特征。因此，针对癌细胞与EV相关的HSP70和HSP90的靶向可能是癌症恶病质的有效治疗策略。但是，动物模型并不总是概括在人类癌症cachexia中发生的复杂事件，验证角色将非常重要人类癌症恶病质中循环HSP70和HSP90的升高，这受到缺乏工具的阻碍在人类中拦截循环HSP70和HSP90。在此R21应用程序中，我们建议检验假设通过具有高疗效，特异性和定义的表位，并确定抗体是否可以在体外和体内改善肌肉浪费人类癌症患者的模型。如果成功，这些抗体可以在以后的临床研究中使用确定拦截升高的循环HSP70和HSP90是否可以改善癌症的肌肉浪费患者。