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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.

项目总结