Dana Farber/Harvard Cancer Center SPORE in Lung Cancer

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PROJECT SUMMARY This application is a resubmission of a Specialized Program of Research Excellence (SPORE) in Lung Cancer originating from the Lung Cancer Program of the Dana-Farber/Harvard Cancer Center (DF/HCC). The DF/HCC SPORE in Lung Cancer includes researchers from multiple Harvard-affiliated hospitals including the Dana- Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC), Brigham and Women’s Hospital (BWH), and Boston Children’s Hospital (BCH), as well as Harvard Medical School (HMS) and Harvard T.H. Chan School of Public Health (HSPH). Previously, the DF/HCC Lung Cancer Program was funded by a Lung Cancer SPORE in 2002. This was followed by a successful renewal application in 2007 and a no-cost extension from 2013-2015. That period of time was accompanied by remarkable productivity by our investigators, including the initial description of epidermal growth factor receptor (EGFR) mutations by investigators at both MGH and DFCI, identification and development of 3rd generation EGFR tyrosine kinase inhibitors (TKIs) which are now in widespread clinical use, and rapid translation of effective ALK/ROS targeted therapies, among other accomplishments. However, despite the immense positive impact of targeted therapies, they have failed to cure advanced lung adenocarcinoma. Over the past 6 years since our prior SPORE ended, the DF/HCC lung program has evolved and grown ever more collaborative. We have maintained a developmental research program to support a new cadre of investigators, who have built strong additional arenas of expertise that add to our longstanding tradition of targeted therapy research in lung cancer, including innate and adaptive immunity, SCLC biology, circulating tumor DNA, and lung cancer screening. The DF/HCC Lung Cancer Program thus seeks SPORE funding to enable integrated teams that capitalize on the strengths of these new and established investigators to achieve our common goal of eliminating lung cancer deaths. The overarching goals of this SPORE are to: A) Design immunologic therapies that harness both the innate and adaptive immune systems to overcome ALK inhibitor resistance and enhance efficacy of PD-1 immune checkpoint blockade in non-small cell lung cancer (NSCLC) (Projects 1 and 2); B) Develop innovative approaches to EGFR and ALK-driven lung cancer with potential to improve long term survival via cancer vaccines or elimination of drug tolerant persister (DTP) cells or cancer vaccines (Projects 1 and 3); C) Co-opt vulnerabilities such as replication stress in SMARCA4 mutant NSCLC or a senescence program in EGFR TKI DTPs (Projects 2 and 3); D) Foster inter-institutional collaboration, including exchange of lung cancer models and patient samples (all Projects); and E) Continue to support and develop the next generation of lung cancer translational scientists from our talented group of fellows and early career investigators, with an emphasis on increasing diversity and equity.