Targeting KLF10 to prevent cancer-associated muscle loss

以 KLF10 为靶点预防癌症相关的肌肉损失

• 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
• 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

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 骨骼肌萎缩影响高达80%的晚期癌症患者，并直接影响手术 预后、化疗反应、发病率、死亡率和生活质量。患者的治疗选择 经历癌症相关的肌肉萎缩/恶病质的患者有限。我们的长期目标是发展和 利用对骨骼肌萎缩的详细分子理解来确定新的治疗模式 限制癌症患者的瘦体重减轻。TGF-β相关信号传导是癌症的公认驱动因素 恶病质，具有许多超家族成员（如激活素A/B、生长分化因子（GDF）和 肌生长抑制素）涉及多种癌症恶病质模型以及人类。尽管与病因有明确的联系 尽管在癌症恶病质中，靶向TGF-β途径的努力尚未取得巨大的临床成功。这种脱节 提供了一个更好地定义癌症恶病质中TGF-β相关信号传导的机会，在此过程中， 确定更好的治疗干预目标。我们目前的初步数据暗示TGF-β靶基因 KLF 10是癌症相关肌肉萎缩的关键介质。我们发现KLF 10的抑制/失活 抑制癌症相关的肌肉萎缩，并进一步证明KLF 10足以驱动 萎缩程序。我们直接将KLF 10与TGF-β相关的萎缩联系起来，并表明KLF 10可以与TGF-β结合， 调节萎缩相关基因（atrogene）MuRF 1。考虑到这些和其他数据，中央 该建议的假设是TGF-β：：KLF 10：：MuRF 1/atrogene信号传导轴促进肌肉萎缩， 荷瘤小鼠。我们将通过完成以下目标来测试这一假设：1）我们将描绘TGF-β 1。 β-相关输入驱动肌肉KLF 10表达和癌症相关肌肉萎缩，2）我们将定义 KLF 10靶点负责浪费相关的表型，3）我们将开发和测试策略， 在临床前癌症恶病质模型中抑制KLF 10。成功完成这些目标将解决一个关键的 关于一个众所周知的萎缩相关信号通路的机械知识缺口，将是一个 这是开发新疗法以对抗癌症相关肌肉萎缩的重要一步。