Lung Adenocarcinoma: From Genome Alterations to Therapeutic Discovery

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Project Summary The introduction of new targeted therapies and immunotherapies has led to significant decreases in lung cancer mortality in the United States in recent years. However, lung cancer continues to kill over 135,000 Americans each year, and over a million people annually world-wide. Thus, there remains an urgent need to continue to improve the prevention, diagnosis and treatment of this deadly disease. Our research focuses on lung adenocarcinoma, the most common form of lung cancer. Lung adenocarcinoma is, at its root, a disease of the genome. The focus of my laboratory is to understand somatic genome alterations in human lung cancer, to use this understanding to elucidate lung cancer pathogenesis, and in turn to improve diagnosis and treatment. We have been honored to participate in many clinically impactful genomic discoveries, including the discoveries of BRAF and EGFR mutations that guide targeted therapy use. In recent work, we continue to advance knowledge of lung cancer genomes and their function. We described novel oncogenic mutations in lung cancer, the duplication of super-enhancer elements near known oncogenes. We analyzed the cancer-causing activity of lung adenocarcinoma mutated genes such as SOS1 and MGA; we initiated genomic approaches to immunological targets such as the ADAR RNA deaminase gene; and we generated a genomically engineered model of aneuploidy for lung cancer. Our proposed research falls into three broad categories: 1. Single gene alterations: we will analyze the mechanisms by which both mutations and copy number alterations underlie the pathogenesis of lung adenocarcinoma. Examples described in this proposal include the tumor suppressor gene CMTR2 and the lineage oncogene NKX2-1, which is the most significantly amplified gene in lung adenocarcinoma. 2. Immunological target identification: we will use genomic approaches to characterize immunological features of lung cancer and potential vulnerabilities. Examples shown here include continued studies of genes involved in RNA sensing & modification in the interferon pathway that are also cancer dependencies, as well as large-scale functional genomic screens to identify epitopes that are antigenic targets of T cells in lung cancer. 3. Genome-wide features. We continue to study aneuploidy and the function of gene dosage effects on cell growth and proliferation. In addition, we are developing a new approach for genome-based therapy: nucleic acid cleavage therapies that target the “neo-genome” in lung cancer DNA. This approach would exploit the novel genomic sequences that result from chromosomal rearrangements in cancer by using genome engineering tools to specifically target cancer cells. My goal is that the knowledge gained from the proposed research will deepen our understanding of human lung adenocarcinoma and will drive novel and effective treatments for lung cancer patients.