Activating mutations in the K-ras proto-oncogene occur in 30% of lung adenocarcinomas, the most commonsubtype of non-small cell lung cancer (NSCLC). K-ras is a membrane-associated GTPase that activatesmultiple kinase pathways, several of which have transforming activity in cellular models. Which of thesedownstream mediators of K-ras contribute to lung tumorigenesis has not been fully elucidated. Moreover, noeffective approaches are available for the treatment of K-ras-mutant NSCLC. To address this problem, weinvestigated a mouse model (K-rasl_A1) that develops lung adenocarcinoma through somatic activation ofoncogenic K-ras (G12D). We observed prominent inflammatory cells (macrophages and neutrophils),vascular endothelial cells, and bronchioalveolar stem cells (BASCs, the putative precursors of lungadenocarcinoma cells) infiltrating atypical alveolar hyperplasia (AAH) lesions and adenomas. This findingindicates that a stromal response induced by oncogenic K-ras accompanies early lung neoplasia. Our globalhypothesis is that oncogenic K-ras-induced lung tumorigenesis is driven in part by a host response to thepresence of transformed alveolar epithelial cells. These cells arise from BASCs and secrete chemokines thatrecruit inflammatory cells and endothelial cells, which, in turn, secrete chemokines and growth factors thatpromote BASC expansion, thereby accelerating lung tumorigenesis. We will test this hypothesis by carryingout two Specific Aims.
In Aim 1, we will use a genetic approach (loss of 3-phosphoinositide-dependentkinase [PDK-1], a PI3K-dependent kinase) to confirm our finding that pharmacologic inhibition of PI3Kdependentsignaling (PX-866 or CCI-779) is sufficient to block lung tumorigenesis induced by oncogenic Kras,and we will examine whether agents that target intra-tumoral endothelial cells (neutralizing CXCR-2antibody) and inflammatory cells (CCI-779) have cooperative anti-tumor effects.
In Aim 2, we will translateour findings in KrasLAI mice to the clinic by examining whether NSCLC patients with K-ras-mutant tumorshave increased serum concentrations of CXCR2 ligands, which thereby mobilize CXCR2pos blood cells intothe circulation. We have established the ability to detect by flow cytometric analysis circulating endothelialcell and CXCR2pos monocytic populations, which we will examine as biomarkers of response to treatmentwith a neutralizing anti-CXCR2 antibody in a Phase I clinical trial in cancer patients.
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