Regulating Neuroendocrine Phenotype in Cancer

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DESCRIPTION (provided by applicant): Neuroendocrine (NE) tumors such as carcinoid and islet cell tumors are the second most common cause of isolated hepatic metastases. These tumors often cause debilitating symptoms due to the excessive hormonal secretion that characterizes 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. We have recently shown that over-expression of raf-1 in human carcinoid and medullary thyroid cancer cells markedly suppresses NE marker expression and serotonin/calcitonin secretion, and silences expression of hASH1, a transcription factor critical to the NE phenotype. In this proposal, we will determine the importance of hASH1 in modulating hormone secretion by human NE cells. Secondly, we will show in preliminary murine studies that raf-1 activation in NE tumors may reduce tumor growth and suppress hormone production. In the second aim, we will develop 2 animal models of recurrent/persistent NE tumor disease to determine if raf-1 activation will inhibit tumor growth and suppress hormone production in vivo. Lastly, we will present data indicating that interleukin-6 may be an essential mediator of raf-1-associated hormone suppression. We will determine if interleukin- 6 is the sole target of raf-1. In summary, these studies should determine if modulation of the raf-1 signal transduction pathway could play a potential role in the management of patients with carcinoid tumors. Furthermore, these finding may permit development of components of raf-1 pathway as therapeutic targets in the treatment and palliation of NE tumors.