Targeting RANKL for the treatment of muscle and bone defects in cachexia

靶向 RANKL 治疗恶病质肌肉和骨骼缺陷

基本信息

批准号：
10273739
负责人：
Andrea Bonetto
金额：
$ 44.18万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-12 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10273739
关键词：
Advanced Malignant Neoplasm Affect Animals Antibodies Atrophic Binding Body Weight decreased Bone Resorption C26 tumor Cachexia Cancer Survivor Cells Cessation of life Chronic Disease Coculture Techniques Colorectal Neoplasms Complication Consequentialism Cyclophosphamide Defect Diagnosis Exhibits Experimental Models Exposure to Fiber Goals Growth Implant In Situ Nick-End Labeling In Vitro Interleukin 6 Receptor Interleukin-6 Ligands Light Malignant Neoplasms Malignant neoplasm of ovary Metastatic Neoplasm to the Bone Mus Muscle Muscle Fibers Muscular Atrophy Musculoskeletal Musculoskeletal Diseases Nonmetastatic Osteoclasts Osteocytes Osteogenesis Osteolysis Osteoporotic Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Play Publishing Quality of life Receptor Activation Recombinants Research Rodent Role Secondary to Skeletal Muscle Symptoms Tumor-Derived Woman Zoledronate bone bone loss bone mass bone preservation cancer cachexia cancer cell chemotherapy circulating biomarkers comorbidity improved in vivo in vivo evaluation mouse model muscle form muscle strength neutralizing antibody new therapeutic target novel ovarian neoplasm overexpression preservation receptor skeletal therapeutic target tumor

项目摘要

PROJECT SUMMARY Cachexia is defined by abnormal loss of body weight and muscle mass that occurs secondary to chronic diseases, such as cancer. It is estimated that musculoskeletal complications affect up to 80% of patients diagnosed with cancer, dramatically impacting patient survival. Thus, there is an urgent need to develop novel treatments for cachexia-related musculoskeletal symptoms. Our recently published observations showing that cancer cachexia can present with bone loss, even in the absence of direct metastases to bone, suggest that tumor-derived soluble factors may play a critical role in the onset of such skeletal phenotype. In this regard, our preliminary findings suggest that receptor activator of NFkB ligand (RANKL), a factor involved in osteoclast- induced bone resorption, plays a causative role in cancer-associated musculoskeletal complications. In our published and preliminary studies we found that patients affected with ovarian cancer present cachexia, as well as elevated RANKL and CTX-I, a marker of bone resorption. Similarly, mice bearing ES-2 ovarian tumors present with muscle and bone loss, along with high RANKL and bone resorption, also consistent with high positivity for the osteoclast marker, TRAP, as well as dramatic osteocyte death. Contrarily, mice carrying C26 tumors, characterized by low RANKL expression, substantially maintain their bone mass, despite evidence of muscle wasting. Interestingly, myotubes exposed to recombinant RANKL undergo atrophy, similar to mice infected with AAV-RANKL or bearing C26 cells overexpressing RANKL, whereas the use of anti-RANKL neutralizing antibodies preserves myotube size in C2C12 myotubes co-cultured with ES-2 cells and counteracts bone and muscle loss in ES-2 tumor hosts. The objective of this proposal is to define the mechanisms by which RANKL-expressing tumors participate in bone and muscle loss in cachexia. Our central hypothesis is that tumor-derived RANKL participates in the activation of bone resorption, and triggers mechanisms adversely affecting muscle mass. In Aim 1, we will determine the effects of tumor-derived RANKL on bone loss in the absence of bone metastases. We hypothesize that tumor-derived RANKL directly activates bone resorption. In Aim 2, we will elucidate the mechanism(s) responsible for RANKL-induced muscle wasting. We hypothesize that activation of the RANKL/RANK-dependent pathway in skeletal muscle is sufficient to induce atrophy and exacerbate cachexia. In Aim 3, we will validate antiresorptive therapies to preserve muscle size and function in mice bearing RANKL-expressing tumors. We hypothesize that tumor-derived RANKL, along with IL-6 consequential to bone resorption, negatively impact muscle. The findings from the proposed studies will define the mechanistic effects of RANKL in cachexia and identify RANKL as a new therapeutic target for the treatment of musculoskeletal complication associated with non- metastatic RANKL-expressing cancers. These results will also open new avenues for cachexia research.

项目概要恶病质是指继发于慢性病的体重和肌肉质量的异常下降。疾病，例如癌症。据估计，肌肉骨骼并发症影响高达 80% 的患者被诊断出患有癌症，极大地影响了患者的生存。因此，迫切需要开发新颖的治疗恶病质相关的肌肉骨骼症状。我们最近发表的观察结果表明即使没有直接骨转移，癌症恶病质也可能出现骨质流失，这表明肿瘤来源的可溶性因子可能在这种骨骼表型的发生中发挥关键作用。对此，我们的初步研究结果表明，NFkB配体受体激活剂（RANKL）是破骨细胞参与的一个因子诱导骨吸收，在癌症相关的肌肉骨骼并发症中起着致病作用。在我们发表的初步研究中，我们发现卵巢癌患者出现恶病质，以及骨吸收标志物 RANKL 和 CTX-I 升高。同样，携带 ES-2 卵巢肿瘤的小鼠存在肌肉和骨质流失，以及高 RANKL 和骨吸收，也与高破骨细胞标记物 TRAP 呈阳性，以及骨细胞急剧死亡。相反，携带C26的小鼠以低 RANKL 表达为特征的肿瘤基本上维持其骨量，尽管有证据表明肌肉萎缩。有趣的是，暴露于重组 RANKL 的肌管会发生萎缩，与小鼠类似感染 AAV-RANKL 或携带过表达 RANKL 的 C26 细胞，而使用抗 RANKL 中和抗体保留与 ES-2 细胞共培养的 C2C12 肌管中的肌管大小并抵消 ES-2 肿瘤宿主的骨和肌肉损失。该提案的目的是确定表达 RANKL 的肿瘤参与恶病质时骨骼和肌肉损失。我们的中心假设是肿瘤衍生的 RANKL 参与激活骨吸收，并触发对肌肉质量产生不利影响的机制。在目标 1 中，我们将确定在没有骨转移的情况下肿瘤衍生的 RANKL 对骨丢失的影响。我们假设肿瘤衍生的 RANKL 直接激活骨吸收。在目标 2 中，我们将阐明其机制负责 RANKL 诱导的肌肉萎缩。我们假设 RANKL/RANK 依赖的激活骨骼肌中的途径足以引起萎缩并加剧恶病质。在目标 3 中，我们将验证抗吸收疗法可保持携带 RANKL 表达肿瘤的小鼠的肌肉大小和功能。我们假设肿瘤衍生的 RANKL 以及导致骨吸收的 IL-6 产生负面影响肌肉。拟议研究的结果将定义 RANKL 对恶病质的机制作用并确定 RANKL作为治疗与非-相关的肌肉骨骼并发症的新治疗靶点表达 RANKL 的转移性癌症。这些结果也将为恶病质研究开辟新途径。