Neuroendocrine (NE) tumors are the second most common cause of isolated hepatic metastases. These tumors often cause debilitating symptoms due to excessive hormonal secretion which characterize these NE lesions. Besides surgery, there are limited curative and palliative treatments available to patients with NE tumors, emphasizing the need for development of other forms of therapy. Notch1 is a multi-functional transmembrane receptor that plays an important role in cellular differentiation in the gastrointestinal (GI) tract. Similar to its role in developing nervous tissues, Notch1 signaling is thought to mediate a process called lateral inhibition within the GI tract. During GI development, multipotent cells destined to differentiate into enteroendocrine cells express the Notch1 ligand, Delta. Delta then binds to Notch1 receptors on neighboring undifferentiated cells. This triggers activation of Notch1 within the undifferentiated cells, leading to a cascade that inhibits the expression of pro-endocrine genes. Thus, the overall effect is to limit the number of cells which can differentiate into enteroendocrine cells. The lab has recently shown that over expression of Notch1 in GI carcinoid cells as well as in medullary thyroid cancer cells causes a dramatic reduction in hormone production accompanied by growth suppression. His group is currently developing animal models of GI carcinoid and medullary thyroid tumor progression to investigate the possible role of Notch1 in suppressing hormone production by these tumors. This group is also initiating clinical trails with Notch1 activating compounds.