Targeting KLF10 to prevent cancer-associated muscle loss

摘要 高达80%的晚期癌症患者骨骼肌萎缩，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 经历与癌症相关的肌肉萎缩/恶病质是有限的。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范例 这限制了癌症患者的瘦体重损失。转化生长因子-β相关信号是癌症的公认驱动因素 恶病质，有许多超家族成员(如激活素A/B、生长分化因子(GDF)和 肌肉抑制素)与多种癌症恶病质模型以及人类的癌症恶病质模型有关。尽管与病因学有明显联系 对于癌症恶病质，靶向转化生长因子-β途径的努力并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转化生长因子-β相关信号的机会，在这个过程中， 确定更好的治疗干预目标。我们提供了与转化生长因子-β靶基因有关的初步数据。 KLF10作为癌症相关肌肉萎缩的关键调节因子。我们发现KLF10抑制/失活 抑制癌症相关的肌肉萎缩，并进一步证明KLF10足以推动 萎缩计划。我们直接将KLF10与转化生长因子-β相关的萎缩联系起来，并表明KLF10可以与 调节萎缩相关基因(萎缩基因)MuRF1。考虑到这些和其他数据，中央银行 这一提议的假设是转化生长因子-β：：KLF10：：MuRF1/阿托金信号轴促进肌肉萎缩。 荷瘤小鼠。我们将通过完成以下目标来检验这一假设：1)我们将描述转化生长因子- 驱动肌肉β表达和癌症相关肌肉萎缩的KLF10相关输入，2)我们将定义 KLF10负责浪费相关表型的目标，以及3)我们将开发和测试策略，以 在临床前癌症恶病质模型中抑制KLF10。这些目标的成功实现将解决一个关键的 关于众所周知的萎缩相关信号通路的机械性知识差距，将是 朝着开发抗击癌症相关肌肉萎缩的新疗法迈出了重要的一步。

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.