Colon cancer continues to be a leading cause of death in men and women. Other than surgical resection no other systemic or adjuvant therapy is available. Cumulative evidence in literature suggests that gastrins play a role in the proliferation of colon cancers. Colon cancer cells express the gastrin gene and a significant percent bind gastrins suggesting an autocrine role of gastrins.
In Aim 1 we will test the hypothesis that gastrin gene products function as autocrine growth factors for colon cancer cells by using antisense strategies. Specific antibodies will be used to assess the functional role of autocrine vs endocrine gastrins.
In Aim 2 we will test the hypothesis that src-like kinases mediate mitogenic/autocrine effects of gastrins. We will use microinjection technology to experimentally test the obligatory role of src-like kinases. Intestinal cells, overexpressing mutated src proteins will also be used. Recent studies suggest that novel receptors (GP-R), that bind both amidated and gly extended gastrins, mediate proliferative effects of gastrins on intestinal cells. Four other receptor-subtypes have been identified that mediate biological effects of gastrin on several target cells.
In Aim 3 we will examine the role of the various receptor-subtypes, including GP-R, in mediating mitogenic effects of gastrins. Since the novel GP-R have yet to be purified and cloned, we will purify GP-R for purposes of peptide sequencing and cDNA cloning in Aim 4. If studies under Aim 1 confirm a functional role of autocrine/endocrine gastrins in the growth and tumorigenicity of colon cancer cells then one can begin to develop treatment strategies that include reduction of gastrin gene expression. If studies under Aim 2 confirm a mediatory role of src PTKs then one can further develop strategies that block the signaling pathway. If we are successful in purifying the novel GP-R (and confirm its role in mediating the mitogenic effects of gastrins) then one can develop systemic strategies to block the receptor mediated effects in future funding periods.
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