Molecular Mechanisms of Cachexia in Lung Cancer

? 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.