Activating mutations in the K-ras proto-oncogene occur in 30% of lung adenocarcinomas, the most common subtype of non-small cell lung cancer (NSCLC). K-ras is a membrane-associated GTPase that activates multiple kinase pathways, several of which have transforming activity in cellular models. Which of these downstream mediators of K-ras contribute to lung tumorigenesis has not been fully elucidated. Moreover, no effective approaches are available for the treatment of K-ras-mutant NSCLC. To address this problem, we investigated a mouse model (K-rasl_A1) that develops lung adenocarcinoma through somatic activation of oncogenic K-ras (G12D). We observed prominent inflammatory cells (macrophages and neutrophils), vascular endothelial cells, and bronchioalveolar stem cells (BASCs, the putative precursors of lung adenocarcinoma cells) infiltrating atypical alveolar hyperplasia (AAH) lesions and adenomas. This finding indicates that a stromal response induced by oncogenic K-ras accompanies early lung neoplasia. Our global hypothesis is that oncogenic K-ras-induced lung tumorigenesis is driven in part by a host response to the presence of transformed alveolar epithelial cells. These cells arise from BASCs and secrete chemokines that recruit inflammatory cells and endothelial cells, which, in turn, secrete chemokines and growth factors that promote BASC expansion, thereby accelerating lung tumorigenesis. We will test this hypothesis by carrying out two Specific Aims.
In Aim 1, we will use a genetic approach (loss of 3-phosphoinositide-dependent kinase [PDK-1], a PI3K-dependent kinase) to confirm our finding that pharmacologic inhibition of PI3Kdependent signaling (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-2 antibody) and inflammatory cells (CCI-779) have cooperative anti-tumor effects.
In Aim 2, we will translate our findings in KrasLAI mice to the clinic by examining whether NSCLC patients with K-ras-mutant tumors have increased serum concentrations of CXCR2 ligands, which thereby mobilize CXCR2pos blood cells into the circulation. We have established the ability to detect by flow cytometric analysis circulating endothelial cell and CXCR2pos monocytic populations, which we will examine as biomarkers of response to treatment with a neutralizing anti-CXCR2 antibody in a Phase I clinical trial in cancer patients.
|Wen, Chi-Pang; Zhang, Fanmao; Liang, Dong et al. (2015) The ability of bilirubin in identifying smokers with higher risk of lung cancer: a large cohort study in conjunction with global metabolomic profiling. Clin Cancer Res 21:193-200|
|Chiappori, A A; Kolevska, T; Spigel, D R et al. (2015) A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. Ann Oncol 26:354-62|
|Mender, Ilgen; Gryaznov, Sergei; Dikmen, Z Gunnur et al. (2015) Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine. Cancer Discov 5:82-95|
|Kim, Eric S; Ye, Yuanqing; Vaporciyan, Ara A et al. (2015) Telomere length and recurrence risk after curative resection in patients with early-stage non-small-cell lung cancer: a prospective cohort study. J Thorac Oncol 10:302-8|
|Fujimoto, Junya; Wistuba, Ignacio I (2014) Current concepts on the molecular pathology of non-small cell lung carcinoma. Semin Diagn Pathol 31:306-13|
|Ludlow, Andrew T; Robin, Jerome D; Sayed, Mohammed et al. (2014) Quantitative telomerase enzyme activity determination using droplet digital PCR with single cell resolution. Nucleic Acids Res 42:e104|
|Lin, Steven H; Wang, Jing; Saintigny, Pierre et al. (2014) Genes suppressed by DNA methylation in non-small cell lung cancer reveal the epigenetics of epithelial-mesenchymal transition. BMC Genomics 15:1079|
|Yang, Yanan; Ahn, Young-Ho; Chen, Yulong et al. (2014) ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism. J Clin Invest 124:2696-708|
|Holohan, Brody; Wright, Woodring E; Shay, Jerry W (2014) Cell biology of disease: Telomeropathies: an emerging spectrum disorder. J Cell Biol 205:289-99|
|Osborne, Jihan K; Guerra, Marcy L; Gonzales, Joshua X et al. (2014) NeuroD1 mediates nicotine-induced migration and invasion via regulation of the nicotinic acetylcholine receptor subunits in a subset of neural and neuroendocrine carcinomas. Mol Biol Cell 25:1782-92|
Showing the most recent 10 out of 647 publications