Lung cancer is the most common cancer and has the highest mortality in the US. Tumor metastasis is the major cause of mortality for non-small-cell lung cancer (NSCLC) patients. About 85%-90% of lung cancers are NSCLC and somatic mutations in oncogenic Ras and the tumor suppressor p53 or LKB1 are frequently detected in NSCLC. Unfortunately effective drugs that directly target Ras, p53 or LKB1 have so far not succeeded for cancer therapy. This project investigates the role of autophagy on Kras-driven lung cancer with the ultimate goal of providing a new strategy for lung cancer therapy. Autophagy is a protective process that is activated in response to stress in order to recycle cellular components to maintain homeostasis. During the last five years in the White laboratory, Dr. (Jessie) Yanxiang Guo discovered that cancer cells with Ras activation require autophagy for maintenance of functional mitochondria, for tolerance of metabolic stress and for tumorigenesis. Using two genetic engineered mouse models (GEMMs) for Kras-driven NSCLC with or without p53 and concurrent deletion of essential autophagy gene, autophagy-related-7, Atg7, Dr. Guo found that autophagy deficiency altered the fate of KrasG12D-induced carcinomas to rare, predominantly benign oncocytomas, caused accumulation of defective mitochondria and reduced the tumor growth. With the additional loss of p53, autophagy deficiency impaired mitochondrial fatty acid oxidation (FAO) resulting in defective lipid homeostasis and exquisite sensitivity to metabolic stress. These results suggest that Ras-driven cancers may be susceptible to autophagy inhibition therapy. In this NIH Transition Career Development Award, Dr. Guo, supported by her mentor Dr. Eileen White and her collaborators, plans to test the central hypothesis that autophagy is important for metabolism and growth of lung cancer in the following specific aims:
Aim 1 is to determine the extent to which suppression of tumor growth by Atg7 deficiency is reversible and how autophagy inhibition differentially impacts tumor compared to normal tissue;
Aim 2 is to determine if autophagy is required to suppress oncocytoma formation and to maintain lipid homeostasis in KrasG12D-driven NSCLC with p53 missense mutations;
and Aim 3 is to determine if and how autophagy inhibition impacts Kras-driven lung cancer metastasis. State-of-the-art metabolomic and lipidomic analysis will be used to determine the mechanism by which autophagy regulates cancer metabolism and growth. This project will develop innovative pre-clinical models to determine the role of autophagy in lung cancer and will identify metabolic vulnerabilities created by the altered metabolism. These findings will provide novel translational approaches for Kras-driven lung cancer therapy by dual inhibition of Ras downstream effector pathways and autophagy. Dr, Guo obtained her formalized research training in Dr. Sally Kornbluth 's laboratory at Duke University where she focused on the regulation of cell cycle and cell death in cancer, earning a Ph.D. degree in Molecular Cancer Biology. Currently, Dr. Guo is an Assistant Research Professor in Dr. White's laboratory at Rutgers Cancer Institute of New Jersey (RCINJ) where she has been studying the function of autophagy in regulating Ras-driven cancer metabolism. Dr. Guo's immediate and long-term career goals are to: 1) become a NIH funded independent investigator focusing on metabolism of lung cancer; 2) develop into a leader of a dedicated group of scientists that focus on lung cancer at an NCI-designated comprehensive cancer center or a world-class research university or institute with an excellent scientific environment; and 3) identify new molecular targets for anti-cancer drugs. Dr. Guo will accomplish these goals with three major components: 1) Laboratory research: Dr. Guo will execute her research plan outlined above with full support from Dr. White. She will also receive support and instruction from her collaborators including: Dr. Josh Rabinowitz, a recognized leader in metabolomics at Princeton University, in the use of metabolomics to interrogate cancer metabolism; Dr. Yibing Kang, a recognized leader in cancer metastasis at Princeton University, in novel approaches to interrogate metastasis; Dr. Arnold Levine, a widely acclaimed leader in cancer research and p53 biology at Institute of Advanced Study and RCINJ, to elucidate p53 function and regulation in cancer; Dr. Chan Chang, an expert in the use of Next Generation Sequencing in the study of genetics of cancer at RCINJ; and Dr. Narita at Cancer Research UK, Cambridge Institute, who is generating an inducible Tet-on-shRNA-Atg5 shRNA mouse model that will be provided to Dr. Guo. 2) Didactics: Dr. Guo has and will continue to receive hands-on metabolomics training provided by Dr. Rabinowitz's group. She will take two courses Introductory XF Training and Advanced XT Training provided by Seahorse Biosciences to study cancer cell metabolism using a Seahorse Bioscience XF Analyzer. She will receive on-site training from Dr. Kang and join his lab meetings to further develop expertise in tumor metastasis. She will also obtain technical advise from Dr. Narita to help successfully generate the Tet-on-shRNA-Atg7 mouse model she proposed. 3) Professional/Leadership Development: Dr. Guo will attend The objective Analysis of Self and Institution Seminar (OASIS): Leadership and Professional Development Program offered by Rutgers University for women to help her develop as a leader in academia.
Lung cancer is the most common cancer and has the highest mortality in both men and women in the US. Oncogenic mutations in Ras are frequent in lung cancer. Unfortunately, all efforts to date to develop drugs that directly target Ras for lung cance therapy have been unsuccessful. I discovered that lung cancers with oncogenic Ras require autophagy for mitochondrial function, survival and tumor growth. In this proposal, I will use genetic engineered mice to model autophagy inhibition in lung cancer therapy, determine the role of autophagy in the context of the most aggressive lung cancers and determine if autophagy is required for metastasis. In doing so I will potentially provide a strategy for lung cancer therapy via autophagy inhibition.
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