Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide (Herbst et al. 2008). Non-small-cell lung cancer (NSCLC), accounts for ~85% of all lung cancer cases. 20-30% of human NSCLC tumors acquire mutations in anti-oxidant transcription factor Nrf2 (gain-of-function (GOF)) or its negativ regulator Keap1 (LOF) suggesting an important role for oxidative stress homeostasis to maintain cancer cell survival during lung carcinogenesis. Despite the high frequency of mutations observed in this pathway, little is know about its role in lung tumor initiation and progression. To study NSCLC our laboratory utilizes a genetically engineered mouse model (GEMM) of NSCLC that faithfully recapitulates the histologic, molecular, progression features of human NSCLC. Tumors develop in the autochthonous (native) tissue context, in the presence of an intact tumor microenvironment and in the absence of confounding tobacco mutagens. I have recently developed a rapid and precise in vivo method that bypasses the need for time- consuming manipulation of the murine germline in order to engineer novel alleles of interest. I have combined the power of sophisticated Cre/loxP-based GEMMs with the highly precise genome editing CRISPR/Cas9 system. Using this powerful new approach I will functionally investigate the tumor cell- autonomous role of Nrf2 and Keap1 in the lung adenocarcinoma initiation and progression using the NSCLC GEMM. The research proposed within this application for a K22 NIH career transition award focuses on elucidating the role of the Nrf2 anti-oxidant pathway in initiation and progression by rigorous in vivo experimental approaches combining both genetic and biochemical approaches. The goals and timeline of these well-defined and achievable experiments outlined within are to: * Dissect the functional importance of Nrf2 in NSCLC tumorigenesis * Identify the metabolic changes mediated by Nrf2 in lung cancer * Identify the Nrf2 targets that are important for mediating its anti-oxidant functions in vivo * Provide a platform for experimental cross talk between observations in NSCLC GEMMs and human cell lines, which will prove valuable for future research The project described within this application has been shaped by my long-standing dedication to the field of cancer biology and more importantly my ongoing efforts in Dr. Tyler Jacks' laboratory to uncover the fundamental mechanisms involved in initiation and progression in this autochthonous mouse model of NSCLC. I have benefited from the research environment in the Jacks Laboratory, MIT, and the surrounding area that offers unmatched opportunities for scientific discussion, collaboration, and training. The scientific community at MIT, the Broad Institute, and Harvard Medical School offers countless seminars and workshops that continue to foster my scientific development. Additionally, I supervise have supervised three undergraduate MIT student, three summer students and two technical assistant that work directly with me on experiments pertaining to the proposed research project. This is an incredible experience that will endow me with many of the necessary skills to manage a laboratory during the independent phase of this award and beyond. This proposal represents my dedicated scientific investment towards identifying the fundamental drivers of NSCLC tumorigenesis, by uniting collaborators' analyses and the use of a sophisticated genetically engineered mouse. It is my intention to start an independent research program that will capitalize on the insight I obtain from the in vivo animal model with the goal to translate my findings in human systems. For the long-term, I am confident that these experiments will provide a solid foundation on which my research program can be built upon. I look forward to educating and recruiting students and postdocs that share my passion for cancer research.
Kras-driven non-small cell lung cancer (NSCLC) remains one of the most aggressive and lethal solid tumors, therapeutic options and outcomes for NSCLC have remained virtually unchanged over the past thirty years. In this proposal we aim to elucidate the role of the anti-oxidant Keap1/Nrf2 pathway, which is mutated in 20-30% of human NSCLC, in a highly relevant genetically-engineered mouse model of NSCLC. This study will integrate genetic and biochemical approaches to study Keap1/Nrf2 function, with the ultimate aim to therapeutically target this pathway in a cancer with great clinical need.
| Sayin, Volkan I; LeBoeuf, Sarah E; Singh, Simranjit X et al. (2017) Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife 6: |
| Romero, Rodrigo; Sayin, Volkan I; Davidson, Shawn M et al. (2017) Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med 23:1362-1368 |
