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Identification of Novel Dependencies in Small Cell Lung Cancer (SCLC) that are a Consequence of Loss of Function Mutations in Tumor Suppressor Genes or from SCLCs Neuroendocrine Differentiation State
Although small cell lung cancer (SCLC) is initially highly responsive to chemotherapy, the disease recurs in nearly all patients in less than a year. At recurrence, there are no approved targeted therapies. Genomic sequencing of human SCLCs has shown that SCLCs have no actionable mutations and that nearly all SCLCs harbor loss of function (LOF) mutations in the tumor suppressor genes RB1 and TP53, while ~25% of SCLCs harbor LOF mutations in NOTCH.  Furthermore, sustained expression of neural/neuroendocrine lineage transcription factors ASCL1 and NEUROD1 are required for SCLC survival. However, ASCL1 and NEUROD1 are transcriptions factors and therefore are not directly druggable.
The Oser laboratory utilizes CRISPR-Cas9 screening approaches to identify new SCLC therapeutic targets that are either required for sustained expression of the neural/neuroendocrine lineage transcription factors ASCL1 and NEUROD1, or that are required for SCLC survival as a consequence of LOF mutations in tumor suppressor genes (i.e. are synthetic lethal interactors with SCLC tumor suppressor genes). In addition, we utilize a novel genetically-engineered mouse model of SCLC developed using CRISPR-Cas9 to study the consequences of inactivating novel candidate therapeutic targets during SCLC tumorigenesis. Ultimately, the Oser laboratory seeks to discover new targeted therapies for SCLC patients that function as synthetic lethal interactors with SCLC tumor suppressor genes or that function to block neuroendocrine differentiation.

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