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Abstract IA3: Lung cancer stem cells, acquired vulnerabilities, and molecular portraits: Translation to the clinic

Recent advances in detailed molecular understanding of lung cancer including complete genome sequences affords the possibility of developing molecularly targeted therapy for potentially all lung cancers. Currently the Lung Cancer Mutation Consortium (LCMC) has developed an integrated approach and network for identifying lung cancers with specific mutations and funneling these patients into clinical trials targeting the specific mutations identified. However, another approach is to use genome wide and chemical library screens to identify genetic and epigenetic changes that have been created in lung cancer cells during tumor pathogenesis that are absolutely required for the activated oncogenic pathways to function. These are often referred to as “synthetic lethal” changes and represent adaptations the cancer cell has to make to allow the “oncogene addictions” to drive tumor growth and survival. They are present in tumor but not normal cells and thus represent “acquired vulnerabilities” that can be therapeutically targeted. The NCI's “Cancer Target Discovery and Development Network” (CTD2N) exemplifies this combined genetic and pharmacologic approach. A most important subgroup of these vulnerabilities are changes that are required for the continued function and survival of a subpopulation of tumor cells that have acquired tumor initiating and often metastatic and drug resistant characteristics including many of the properties of stem cells that are referred to as cancer stem cells (CSCs) or “cancer initiating cells.” To achieve these goals we have developed a large integrated research platform. We have also: developed assays for identifying lung CSCs, “molecular portraits” (clades) that group lung cancers into subsets of clinical and molecular relevance; genome wide siRNA and chemical library functional screens to test for portrait/clade specificity. From these efforts we have learned that: There are a subset of cells within lung cancers (ranging from 0.1–30% of non small cell lung cancers, NSCLCs) and 50% + of small cell lung cancers, SCLCs) identified by elevated aldehyde dehydrogenase (ALDH) activity that have dramatically enhanced clonogenic, tumorigenic, and self renewal capacity; Patients whose tumors are enriched is such ALDH+ tumor cells have significantly impaired prognosis; The notch pathway (particularly Notch3) and ALDH1A3 are major vulnerabilities in lung CSCs; NSCLCs can be subdivided by mRNA expression profiles into “molecular portraits” (or “clades”) that have relevant clinical, oncogenotype, and drug response phenotypes; Genome wide siRNA and large chemical library screens identify targets that are specific for lung cancer over normal lung epithelial cells; The identified targets show dramatic clade and oncogenotype specificity as well as specificity for lung cancers with different responses to available chemotherapy and targeted therapy for lung cancer; The newly identified vulnerabilities provide coverage of essentially all lung cancers and as such, provide a new functional “vulnerability classification” of lung cancer. All of these findings set the stage for the development of a rational approach to developing therapy targeted at lung cancer acquired vulnerabilities including those in lung CSCs that will include personalizing the therapy for each patient. (Supported by Lung Cancer SPORE P50CA70907, DOD Prospect, CPRIT, and NCI CTD2N CA148225.)