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Targeting KLF10 to prevent cancer-associated muscle loss

以 KLF10 为靶点预防癌症相关的肌肉损失

基本信息

批准号：
10928953
负责人：
Jason Doles
金额：
$ 23.92万
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：
2023
资助国家：
美国
起止时间：
2023-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10928953
关键词：
Address Advanced Malignant Neoplasm Affect Anabolism Atrophic Automobile Driving Binding Biochemistry Biological Assay Cachexia Cancer Etiology Cancer Model Cancer Patient Catabolism Cells ChIP-seq Clinical Complex Cues Data Differentiation and Growth GDF8 gene Gene Expression Genes Genetic Goals Human Impairment In Vitro Knockout Mice Knowledge Ligands Link Malignant Neoplasms Mediator Mission Modeling Molecular Molecular Biology Molecular Target Morbidity - disease rate Mus Muscle Muscle Fibers Muscle satellite cell Muscular Atrophy Mutagenesis Myomatous neoplasm Natural regeneration Operative Surgical Procedures Pathway interactions Patient-Focused Outcomes Patients Phenotype Prevention Process Production Prognosis Quality of life RNA Interference Reporter Signal Pathway Signal Transduction Skeletal Muscle Skeletal Muscle Neoplasm Source Syndrome Testing Therapeutic Intervention Thinness Tissues Transforming Growth Factor beta Transplantation Wasting Syndrome activin A bone cancer cachexia chemotherapy combat conditional knockout experience fat wasting functional decline improved in vivo malignant muscle neoplasm member morphogens mortality mouse model muscle hypertrophy novel novel therapeutics pre-clinical preservation prevent programs promoter public health relevance receptor repaired response satellite cell skeletal muscle wasting small hairpin RNA small molecule success targeted treatment therapeutic target therapeutically effective therapy design tool treatment response treatment strategy tumor wasting

项目摘要

ABSTRACT Skeletal muscle wasting affects up to 80% of patients with advanced cancer and directly impacts surgical prognosis, chemotherapeutic response, morbidity, mortality, and quality of life. Treatment options for patients experiencing cancer-associated muscle wasting/cachexia are limited. Our long-term goal is to develop and leverage a detailed molecular understanding of skeletal muscle wasting to identify novel treatment paradigms that limit lean mass loss in cancer patients. TGF-β-associated signaling is a well-established driver of cancer cachexia, with many superfamily members (such as Activins A/B, Growth-Differentiation Factors (GDFs), and Myostatin) implicated in multiple cancer cachexia models as well as in humans. Despite clear links to the etiology of cancer cachexia, efforts to target the TGF-β pathway have not achieved great clinical success. This disconnect presents an opportunity to better define TGF-β-associated signaling in cancer cachexia, and in the process, identify better targets for therapeutic intervention. We present preliminary data implicating the TGF-β target gene KLF10 as a key mediator of cancer-associated muscle wasting. We show that KLF10 suppression/inactivation suppresses cancer-associated muscle wasting and further demonstrate that KLF10 is sufficient to drive the atrophy program. We directly link KLF10 to TGF-β-associated atrophy and show that KLF10 can bind to and regulate the atrophy-associated gene (atrogene) MuRF1. Considering these and other data, the central hypothesis of this proposal is that a TGF-β::KLF10::MuRF1/atrogene signaling axis promotes muscle wasting in tumor-bearing mice. We will test this hypothesis by completing the following objectives: 1) we will delineate TGF- β-associated inputs that drive muscle KLF10 expression and cancer-associated muscle wasting, 2) we will define KLF10 targets responsible for wasting-associated phenotypes, and 3) we will develop and test strategies to inhibit KLF10 in pre-clinical cancer cachexia models. Successful completion of these aims will address a critical mechanistic knowledge gap regarding a well-known atrophy-associated signaling pathway and will be a significant step towards developing novel therapies to combat cancer-associated muscle wasting.

摘要