Abstract CN01-03: Moving from molecular biology to clinical prevention in colorectal cancer
Authors: Grady William M. 
Published: June 2012

Abstract
Cancers of the gastrointestinal tract are among the most common cancers affecting people around the world. Colorectal cancer, stomach cancer, and liver cancer are the most prevalent GI cancers and are not effectively treated with currently available medical therapies, which has led to intense efforts to try to prevent these cancers from occurring. These efforts have led to a better understanding of the molecular and cellular biology of the tumors and to the identification of clinically effective chemoprevention agents for at least some of these cancers. Our understanding of the molecular biology of colorectal cancer and how it interfaces with prevention strategies is arguably more advanced than it is for most other tumors types. Thus, the focus of this session will be on colorectal adenoma and cancer prevention. The molecular biology related to clinically effective primary and secondary chemoprevention will be discussed as will promising future strategies based on our understanding of the molecular pathogenesis of colorectal cancer.
Colorectal cancer is known to evolve through a series of histologic progression steps called the polyp cancer sequence. These histologic steps include early adenomas, advanced adenomas, early adenocarcinomas and advanced adenocarcinomas. These steps result from the accumulation of genetic and epigenetic alterations in colon epithelial cells, which drive the initiation and progression of colorectal cancers. Genes identified to be mutant early in the polyp-cancer sequence include APC, KRAS, and BRAF, and these mutant genes are logical targets for chemoprevention strategies. With regards to epigenetic alterations, aberrant DNA CpG island hypermethylation has been shown to occur at the earliest steps of polyp formation. The consequence of the genetic and epigenetic alterations is to deregulate a number of signaling pathways, including the Wnt-APC-ß-catenin pathway, KRAS-MAPK pathway, TGF-ß pathway, and PI3K pathway, and to disrupt metabolic processes in the cells, including glycolysis, proliferation, apoptosis and senescence, and differentiation.
Although a large number of drugs, nutritional supplements, and whole foods (ie vegetables, fiber, green tea) have been assessed for their chemoprevention properties, the most robust data is available for NSAIDs, anti-oxidants, calcium, vitamin D, DMFO, and folate. NSAID's inhibit COX-2, an enzyme involved with conversion of arachidonic acid to tumor-promoting prostaglandins that is expressed at high levels in the majority of colon adenomas and cancers. COX-2 is presumably a major target of NSAID's although other non-COX-2 related mechanisms also likely play a role in NSAID mediated chemoprevention. Vitamin D and calcium inhibit cell proliferation and induce differentiation and apoptosis. The effects on the molecular biology of nascent tumor cells is less clear for these agents than it is for NSAID's. The most recent agent shown to be clinically effective for secondary adenoma prevention is DFMO, which inhibits ornithine decarboxylase and affects polyamine production. Folate's role in chemoprevention is unclear at this time in light of data that suggests the timing of its use in relation to tumor initiation may play a major role in whether it inhibits or promotes colon cancer formation. Lastly, anti-oxidants presumably mediate their effects through reducing DNA-damaging free radicals, although clinically they do not appear to be effective chemoprevention agents. The clinical efficacy of some of these candidate agents suggests further efforts to target the molecular mediators of these agents will enhance future chemoprevention strategies. In addition, advances in our understanding of the molecular pathogenesis of colorectal cancer has suggested additional strategies for colorectal cancer chemoprevention, such as drugs that inhibit ß-catenin induced gene expression, etc., that may be effective and selective for the early neoplastic cells.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN01-03.