. This proposal describes plans for the candidate's transition from the mentored to the independent phase of the Pathway to Independence K99/R00 award. Throughout the K99 phase of this award the candidate was mentored by Dr. Harold Varmus at Memorial Sloan-Kettering Cancer Center (MSKCC). During this time she developed her independent research program, built on her scientific knowledge and obtained a tenure-track Assistant Professor position (beginning in July 2010) at Yale University in the Department of Pathology and membership in the Yale NCI-designated Comprehensive Cancer Center. For the ROO independent phase of this award. Yale University will provide institutional support, including ample resources, career development activites and opportunities for interactions between scientists and clinicians to help the candidate achieve her goals. The research focuses on lung cancer, the most common cancer worldwide. The candidate has generated two mouse models of lung cancer based on expression of mutant Epidermal Growth Factor Receptors (EGFRs) in lung epithelial cells. She has established that the lung cancer-associated EGFR mutants can initiate lung tumorigenesis, are required for tumor maintenance and has modeled drug resistance in these mice. The goats of this research proposal are to detemnine how the phenotype and clinical behaviour of EGFR mutant lung tumors are influenced by: 1) the levels of expression of mutant EGFR;2) the presence of other EGFR family members;and, 3) cooperating genetic lesions.
The specific aims are to use these new mouse models to: 1) Elucidate the mechanisms of mutant EGFR-induced transfomnation of lung epithelial cells;and, 2) Identify genes that cooperate with mutant EGFR in lung tumorigenesis. Findings in the mouse models will be verified in human lung cancer specimens.
EGFR mutations are found in approximately 10% of non-small cell lung cancer cases in the US and are associated with sensitivity to EGFR tyrosine kinase inhibitors. This proposal addresses questions directly relevant to this subset of lung cancers: 1) How do the EGFR mutants transform lung cells?;and, 2) What are the causes of primary and acquired resistance to tyrosine kinase inhibitor treatment?
|de Bruin, Elza C; Cowell, Catherine; Warne, Patricia H et al. (2014) Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov 4:606-19|
|Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling et al. (2014) Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep 7:999-1008|
|Pirazzoli, Valentina; Politi, Katerina (2014) Generation of drug-resistant tumors using intermittent dosing of tyrosine kinase inhibitors in mouse. Cold Spring Harb Protoc 2014:178-81|
|Lee, Ho-June; Schaefer, Gabriele; Heffron, Timothy P et al. (2013) Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov 3:168-81|
|Politi, Katerina; Lynch, Thomas J (2012) Two sides of the same coin: EGFR exon 19 deletions and insertions in lung cancer. Clin Cancer Res 18:1490-2|
|Politi, Katerina; Pao, William (2011) How genetically engineered mouse tumor models provide insights into human cancers. J Clin Oncol 29:2273-81|