Our overall goal is to identify new, safer, and better-tolerated anti-angiogenic therapies for lung cancer treatment. While therapies targeting tumor cells or tumor-associated vasculature are currently in place for the treatment of lung cancer, they have major limitations, including: 1) the development of resistance; 2) the development of hypertension, proteinuria, and bowel perforation following anti-angiogenic therapy; and 3) most patients still die from primary or metastatic disease. These limitations underscore an urgent need for new, safer, and better-tolerated therapies for the treatment of this devastating disease. This proposal focuses on the contribution of two different, but linked, classes of molecules that can affect lung cancer progression, namely the cytochrome P450 arachidonic acid CYP2C epoxygenases and the nuclear peroxisomal proliferator activated receptor alpha (PPAR?). We aim to: a) provide evidence that whereas the CYP2C are pro-tumorigenic enzymes, PPAR? functions as a new anti-tumorigenic gene, and b) test the novel hypothesis that the anti-tumorigenic activity of PPAR? ligands resides in their ability to downregulate CYP2C expression in a PPAR?-dependent fashion. To this end, we provide evidence that: 1) the endothelial CYP2C epoxygenase metabolites (EETs) are pro-angiogenic in vitro and in vivo; 2) reduction in EET levels inhibits tumor growth and angiogenesis; 3) disruption of the murine Cyp2c44 gene, or its downregulation via PPAR? activation, reduces endothelial cell function in vitro and tumor growth and vascularization in vivo; 4) the human CYP2C9, the metabolic homologue of Cyp2c44, is upregulated in the vasculature of human NSCLC; and 5) two CYP2C9 variants, namely CYP2C9*2 and CYP2C9*3, show markedly reduced pro-angiogenic EET biosynthetic activity. In this proposal we will determine: a) if PPAR? ligands can be viewed as a new class of safer and better-tolerated anti-angiogenic and/or anti-tumorigenic drugs; b) the contribution of Cyp2c44 and PPAR? to the initiation, growth, and progression of lung cancer by utilizing a spontaneous and a human orthotopic model of non small cell lung cancer (NSCLC); and c) if changes in the frequency of the CYP2C9*2 and CYP2C9*3 variants in DNAs from a cohort of NSCLC patients are associated with decreased incidence and/or progression of NSCLC due to their reduced EET synthase activity. Specifically, we will study in Aim 1 the role of Cyp2c44 in the development of primary NSCLC; in Aim 2 the contribution of human PPAR? and its ligand activation to the progression of NSCLC; and in Aim 3 associations between NSCLC and variants in human CYP2C9 and PPAR? genes. These studies may serve as prelude to future clinical studies to validate the usefulness of PPAR? ligands as new, effective, and safer anti-angiogenic agents for cancer treatment. In addition, they might lead to a paradigm shift regarding the role of P450 in cancer: from its known role in anti-cancer drug metabolism to that of a key participant in the biology of tumor growth/angiogenesis and thus a potentially valuable target for anti-cancer drug development.