2018 LCRF Scientific Grant Program
Yanxiang Guo, MD, PhD
Rutgers Cancer Institute of New Jersey
Elucidating the mechanism of autophagy in supporting Lkb1-deficient lung tumorigenesis
Lung cancer remains the leading cause of cancer death worldwide and non-small cell lung cancer (NSCLC) accounts for more than 85% of these cases. Patients harboring mutations in the tumor suppressor liver kinase B1 (LKB1) and the oncogene KRAS, two of the most common mutations in NSCLC, develop more aggressive lung tumors and have limited treatment options. Thus, new therapies for this subtype of lung cancer are urgently needed.
Sufficient energy production is indispensable for tumor growth, and cancer cells have distinct metabolism compared to normal tissues. Thus, targeting cancer metabolism has recently been considered a very important approach to cancer treatment. The catabolic process of autophagy is a protective process that is activated in order to recycle cellular components to maintain energy homeostasis when extracellular nutrients are limited. Using mouse models for LKB1-deficient KRAS-mutant NSCLC, Dr. Guo found that autophagy ablation reduced the frequency of tumor initiation, inhibited tumor growth and extended tumor bearing mouse life span. In this project, Dr. Guo will further elucidate the underlying mechanism by which autophagy maintains energy homeostasis for LKB1-deficient KRAS-mutant lung tumorigenesis using mouse models, metabolomics, lipidomics, quantitative metabolic flux analysis and combination thereof. The overall goal of this project is to find new therapeutic approaches that can be used to effectively treat LKB1-deficient KRAS-mutant NSCLC.