Novel therapeutic development for small cell lung cancer

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PROJECT SUMMARY / ABSTRACT Small cell lung cancer (SCLC) is characterized by rapid growth, early dissemination, and exceptionally poor prognosis. The Rudin laboratory has focused on the study of SCLC for over 2 decades using a fully integrated platform of basic discovery and clinical translational research. Our laboratory has driven fundamental advances in the understanding and characterization of SCLC. We have excelled in successfully translated many discoveries made by our group into clinical testing, including many active trials currently being conducted by our clinical team. Closing the circle, we are also deeply engaged in the molecular characterization of biospecimens from patients receiving these novel therapies, to better inform new directions of laboratory research while maintaining direct disease relevance. In this R35 we will focus primarily on three main areas of future focus for our group. (1) Recent extensive single cell profiling data from our laboratory has defined the exceptional intra- and inter-tumoral heterogeneity of primary human SCLC. We have identified a key subpopulation with stem-like capacity, present in tumors of all SCLC subtypes, and also identified and characterized a novel tumor-infiltrating macrophage subtype exclusively associated with SCLC. The stem-like cell population expands progressively in nodal and distant metastases, and high fraction of this subpopulation confers a strikingly poor clinical prognosis. Defining, characterizing, and targeting these novel cell types could have a transformative impact on patients with SCLC. (2) We have a long-standing interest in lineage plasticity, including histologic transformation from lung adenocarcinoma to SCLC, and tumor evolution between SCLC subtypes. We now have multiple relevant tools in hand to dissect the biology of lineage plasticity in lung cancer, including patient-derived xenograft (PDX) models of lung adenocarcinoma that under different conditions transition to different subtypes of SCLC. We will deeply analyze the drivers of SCLC transformation as a mechanism of tumor escape and acquired resistance in lung cancer. These data will inform approaches to prevent or restrict lineage plasticity as a driver of therapeutic resistance. (3) We have developed new technology allowing controlled in vivo CRISPR/Cas9 gene editing in PDX. We will adapt this system to conduct focused SCLC genetic dependency screens in vivo using a guide RNA library covering the druggable genome. Applied across all subtypes of SCLC, this approach will define novel therapeutic targets for this recalcitrant malignancy.