Pilot: Validation of Peripheral Blood Exosome Lipid Biomarkers in Lung Cancer and IBD

Our overall goal is to develop a blood-based (liquid biopsy) method based on exosomal lipids to accurately discriminate distinct benign diseases as well as provide the means for early detection of malignant disorders. An operationally simple, relatively non-invasive liquid biopsy approach would be of considerable clinical value in helping physicians make accurate diagnosis and thus determine optimal therapy. Peripheral blood exosomes (PBEs) were isolated from plasma taken from 1) active ulcerative colitis (UC), 2) patients with non- small cell lung cancer (NSCLC) and 3) healthy controls (C) and lipids analyzed by ultra-high-resolution mass spectroscopy (UHRMS). State of the art statistical analysis of PBE lipids from normal control, UC and NSCLC patients showed good classification. Specifically, two statistical learning methods, LASSO and random forest, were independently used to select informative lipid features and build classification models. To further apply this approach to the development of clinical assay development in benign and malignant diseases, we aim to answer the following questions: First, (Aim 1), Will the PBE lipid classifiers identified in these studies be validated in a set of new samples (i.e. NSCLC, UC and C)? Second (Aim 2), will PBE lipid classifier signatures discriminate malignant NSCLC from underlying COPD and UC from infectious colitis (Clostridium difficile). These comparisons will be critical to testing the paradigm that PBE classifiers segregate between pre- malignant and malignant disorders as well as infectious and autoimmune benign disorders. The discrimination between these patient subsets will greatly enhance the progression of this technology. Our goal is to use these lipid classifiers as biomarkers to inform clinicians making diagnostic and treatment decisions for patients with benign and malignant conditions. These “proof of concept” studies will address fundamental questions that remain unanswered in the application of PBE lipid classifier technologies to clinical diagnostic testing of benign and cancerous disease. If validated, these approaches will be used to acquire funding from NIH (RO1 and SPORE) and VA sources. More importantly, answers to these crucial questions are needed before this novel and potentially impactful technology can be applied to clinical paradigms. The likelihood of clinical application will need to be determined before this platform can be commercialized. RELEVANCE (See instructions): The current proposal addresses key questions in our quest to develop highly sensitive and specific assays for disease activity and cancer progression. The technology focuses on a metabolic outcome of disease measurable by a simple blood test (“liquid biopsy”). Validation of this approach will support the clinical application of this approach to diagnosis and disease assessment of benign and cancerous conditions.