I earned my Ph.D. in the laboratory of Dr. Vincent Cryns at Northwestern University where I focused on mechanisms of apoptotic cell death in breast cancer. Currently, I am a postdoctoral fellow in the laboratory of Dr. Eileen White at the Rutgers Cancer Institute of New Jersey where I am studying the role of autophagy in lung tumorigenesis in vitro and in vivo. I discovered that autophagy sustains the growth of BrafV600E-driven tumors by maintaining mitochondrial glutamine metabolism. Autophagy ablation in these animals results in an accumulation of defective mitochondria, alteration in tumor cell fate from adenocarcinomas to benign oncocytomas, and an increase in overall survival. This work establishes a functional link between autophagy and the continued growth of lung tumors, suggesting that autophagy inhibition would be a valuable therapeutic strategy in these tumors. I would like to expand on these exciting results as an independent investigator. My research program will be devoted to the study of autophagy in cancer, with an emphasis on how to modulate the pathway as a therapeutic modality in cancer. I have already taken a significant step in this direction by conducting an shRNA screen for autophagy modulators to identify novel mechanisms of autophagy regulation. I identified many vesicle trafficking components, in particular a subset of the Rab GTPases, central organizers of intracellular trafficking, and metabolically relevant genes, such as kinases involved in lipid metabolism, which are predicted to be therapeutic targets for autophagy related diseases and cancer. I am now studying the mechanisms of autophagy regulation and investigating the functional significance of suppressing autophagy by these genes in mouse models of NSCLC. Receipt of the K22 award at this point in my career would provide protected time to gain additional experience and move into new research areas, as well as generate additional data and papers necessary to successfully compete for an R01, thus ensuring my success as an independent investigator. Project Summary Autophagy is a catabolic process that sustains metabolism by recycling intracellular components for use in biosynthetic processes and eliminating damaged proteins and organelles whose accumulation is toxic. It is increasingly clear that tumor cells exploit autophagy as a means to meet their elevated metabolic demands. I discovered that autophagy is required to support mitochondrial metabolism and growth of lung tumors driven by oncogenic BrafV600E. Autophagy ablation resulted in alteration of tumor cell fate and prolonged survival. Similar results have been obtained with lung tumors driven by Kras; and mammary tumorigenesis is blunted in mouse models with deficiencies in components required for nucleation of the autophagosome suggesting that autophagy inhibition is likely to be a powerful therapeutic approach for cancer. This project determines the mechanism of autophagy inhibition by two of the most promising novel autophagy regulators identified by my shRNA screen, the small GTPase Rab9 and the pseudokinase Trib3, and evaluates whether these genes can alter tumor progression and survival in a mouse model of NSCLC. Rab9, a member of the Ras-related small GTPase superfamily, regulates traffic between the late endosome and the trans Golgi network. I hypothesize that it inhibits autophagy by diverting components needed for phagophore nucleation to the endosomal pathway, or by interfering with lipid donation to the expanding autophagosome. The pseudokinase Trib3 plays a central role in lipid homeostasis by controlling the stability of acetyl-coA carboxylase (ACC) and by inhibiting the master regulator of adipogenesis, PPAR?. I hypothesize that Trib3 enhances cellular energy levels to obviate the need for autophagy. These studies are important, and have the potential to identify novel biological mechanisms and approaches to lung cancer therapy as well as extend our understanding of the mechanics and regulation of autophagy.
Lung cancer is the second most frequently diagnosed cancer, and is responsible for the greatest number of cancer fatalities annually. Yet lung cancer remains poorly understood and current treatments are insufficient to save the lives of patients. I discovered that autophagy sustains mitochondrial metabolism, supporting proliferation and growth of Braf-driven lung cancer. Autophagy ablation resulted in progressive mitochondrial dysfunction, decreased tumor burden and was associated with an increase in overall survival, indicating that autophagy inhibition is an important and novel treatment for lung cancer. This project identifies novel autophagy inhibitors from an shRNA screen, defines their mechanism of action, and evaluates their ability to alter autophagy, metabolism, and tumorigenesis in a genetically engineered mouse model of lung cancer. These experiments will enhance our understanding of autophagy and uncover new therapeutic targets for lung cancer.