Molecular Mechanisms of Cachexia in Lung Cancer

 描述(申请人提供)：肺癌是一种毁灭性的疾病，预后很差。尽管出现了早期发现和靶向治疗，但仍需要能够改善结果的干预措施。恶病质是一种综合征，其特征是由于伴随着恶性肿瘤的发展和生长而导致的瘦体重和脂肪质量减少而导致的意外体重下降。恶病质还与肺癌患者的生活质量显著下降、治疗反应差和生存率下降有关。研究人员试图确定恶病质的潜在分子机制，希望将这些发现转化为治疗；然而，将炎症作为减少恶病质的一种手段的尝试基本上没有成功。最近，我们有了一个新的发现，癌细胞分泌细胞外小泡，EV(微囊泡/外切体)，其中含有能够与微环境中的细胞融合的microRNA。我们也已经确定，这种现象延伸到肌肉。我们已经证明，肿瘤细胞分泌的微囊microRNAs，特别是miR-21，能够通过TLR-8/7依赖的途径诱导成肌细胞死亡，从而导致恶病质。我们假设肺癌相关恶病质患者有一种独特的微泡/外体miRNA表达模式，肿瘤相关囊泡miRNAs(包括miR-21)通过TLR依赖的机制诱导肌肉细胞死亡，从而导致恶病质。在目标1中，我们将证明EV microRNAs在癌症相关恶病质小鼠模型中调节失调。我们还将使用基因工程小鼠模型来研究TLR信号作为中心机制的作用。我们建议在临床前模型中对外体microRNAs进行量化。将利用用于捕获和表征的创新技术，以多学科的方式对携带肺肿瘤的小鼠的肿瘤所分泌的微囊/外切体进行量化。在目标2中，我们将证明肺癌患者恶病质的发展与其微泡/外体miRNAs循环水平之间的相关性。我们建议检测一组晚期肺癌患者(N=200)的循环microRNAs。我们的目标将是开发一种肺癌相关恶病质的特征，可用于治疗过程中的预后和监测目的。在目标3中，我们将证明在体内使用适配子靶向选择微囊/外体miRNAs将减少恶病质。我们建议在肺癌荷瘤小鼠中使用适配子抑制选择的miRNAs(miR-21)的加工。

 DESCRIPTION (provided by applicant): Lung cancer is a devastating disease that carries a poor prognosis. Despite the advent of early detection and targeted therapeutics, interventions that can improve outcome are still needed. Cachexia is a syndrome characterized by unintended weight loss resulting from a reduction in lean body mass and fat mass that accompanies the development and growth of malignant tumors. Cachexia is also associated with a significant decline in quality of life, poor response to therapies and reduced survival in lung cancer. Investigators have sought to identify the underlying molecular mechanisms for cachexia with the hopes of translating these findings into therapy; however, attempts at targeting inflammation as a means for reducing cachexia have been largely unsuccessful. Recently, we made the novel discovery that cancer cells secrete Extracellular Vesicles, EV, (microvesicles/exosomes) containing microRNAs that can fuse with cells in the microenvironment. We have also determined that this phenomenon extends to muscle. We have shown that microvesicle microRNAs, particularly miR-21, secreted by tumor cells are capable of inducing cell death in myoblasts by a TLR-8/7 dependent pathway thus leading to cachexia. We hypothesize that patients with lung cancer associated cachexia have a distinct pattern of microvesicle/exosome miRNA expression and that tumor associated vesicle miRNAs (Including miR-21) induce muscle cell death by a TLR- dependent mechanism leading to cachexia. In aim 1, we will demonstrate that EV microRNAs are dysregulated in murine models of cancer associated cachexia. We will also examine the role of TLR signaling as a central mechanism using genetically engineered murine models. We propose to quantify exosomal microRNAs in preclinical models. The quantification of the secreted microvesicles/exosomes by the tumor in lung tumor-carrying mice will be conducted in a multidisciplinary manner leveraging innovative technologies for capture and characterization. In aim 2, we will demonstrate a correlation between the development of cachexia in patients with lung cancer and their circulating levels of microvesicle/exosome miRNAs. We propose to examine circulating microRNAs in a cohort of patients with advanced stage lung cancer (N=200). Our goal will be to develop a signature for lung cancer associated cachexia that may be applied for prognostic and surveillance purposes during the course of therapy. In aim 3, we will demonstrate that targeting select microvesicle/exosome miRNAs in vivo using aptamers will reduce cachexia. We propose to inhibit processing of select miRNAs (miR-21) using aptamers in lung tumor bearing mice.