Emerging evidence indicates that there are gender-specific differences in the biology of lung cancer and in the therapeutic response to new molecularly-targeted agents. Women, particularly non-smokers, are more likely to develop bronchioalveolar carcinoma (BAC), and their disease appears to be more responsive to inhibitors of the epidermal growth factor receptor (EGFR) pathway. A recent trial suggests that men derive greater benefit from the angiogenesis inhibitor bevacizumab, a drug that blocks vascular endothelial growth factor (VEGF), when it was given in combination with chemotherapy. Furthermore, we have recently completed two randomized phase II trials of the dual VEGF/EGFR inhibitor ZD6474 with chemotherapy and observed that women appeared to derive greater benefit than men from this agent (Heymach et al, Proc ASCO 2006; Heymach et al, Proc ASCO 2007). The goals of this grant are to investigate the molecular basis for these gender differences in the formation of BAC, and to learn why women and men with lung cancer respond differently to angiogenesis inhibitors such as bevacizumab and ZD6474. We hypothesize that interactions between EGFR and estrogen receptors (ER) are critical for these differences, and will investigate this hypothesis using both cell lines and mouse models. This work has the potential to expand our understanding of how BAC develops, and to provide a means to identify who is most likely to benefit from antiangiogenic therapy and potentially to increase this benefit by intervening in these critical pathways.