One quarter of persons with adenocarcinoma of the lung develop brain metastases. The central nervoussystem is also emerging as a major site of first relapse after initial success with drugs targeting EGFR.Despite treatment, two thirds of patients with cerebral metastases experience neurological symptoms andmany succumb to this manifestation of lung cancer. Animal model systems of brain metastasis are few. As aresult, little is known about the genes and functions that enable lung adenocarcinomacells to colonize thebrain. We have combined the power of unbiased DNA array-based profiling of gene expression with in vivofunctional selection of organ-specific metastatic cells to identify genes that mediate organ-specificmetastasis. We previously validated this experimental strategy in studies on breast cancer metastasis tobone and lung. Our results to date show that tumor cells utilize different sets of genes to colonize differentorgans. We are applying this approach to the problem of brain metastasis by lung adenocarcinoma cells. Bymeans of in vivo selection of brain metastatic subpopulations from H2030 lung adenocarcinoma cells, andcomparative transcriptomic analysis, we have identified a lung-to-brain metastasis signature consisting ofgenes whose expression is linked to brain metastatic behavior. Building on this preliminary work, we willexpand the identification of brain-specific lung cancer metastasis genes to other KRAS mutant and EGFRmutant cell lines, and to malignant cells from pleural effusions and mediastinal lymph nodes from MSKCCpatients. We will functionally validate brain-specific metastasis genes in brain metastasis assays in mice. Incollaboration with Marc Ladanyi (Core A), we will determine the association of the experimental lung-to-brainmetastasis signature with the clinical outcome of brain metastasis. We will determine which of the lung-to-brain metastasis signature genes mediate disruption of the blood brain barrier and invasion of the brainparenchyma. Based on these cell lines and genes we will develop preclinical models for testing theeffectiveness of, and resistance to, the therapeutic agents studied by Harold Varmus (RP4), William Pao(RP3), and Neal Rosen (RP2). Thus, we will combine unique experimental approaches, novel technologiesand complementary collaborations within this Program Project to identify the determinants of lungadenocarcinoma brain metastasis and its susceptibility to therapeutic intervention.
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