Mutations in Ras are associated with 50% of colorectal carcinomas, indicating the importance of aben'ant Ras activation in tumor development and progression. Recently, mutations in B-Raf, the downstream target of Ras, have been identified in 10% of colorectal carcinomas. The presence of B-Raf mutations in tumors distinct from those with Ras mutations indicates that these mutations are genetically equivalent, such that either one confers a similar advantage. These data support the critical contribution of the Raf>MEK>ERK mitogen-activated protein kinase cascade in Ras-mediated oncogenesis. CmTently, pharmacologic inhibitors of two kinases in this cascade, Raf and MEK, have been developed and are under evaluation in clinical trials. Such target-based drugs are believed to represent the key future direction for anti-cancer drug discovery. However, one major complication that has slowed the clinical development of target-based anti-cancer drugs (e.g., epidermal growth factor receptor inhibitors) is continued uncertainty regarding whether aberrant activation of the target alone is sufficient to define the patient population that will be responsive to these drugs. This uncertainty is based, in part, on the fact that the presence of an altered target may simply have a correlative, rather than a causal, role in oncogenesis. Based on observations in preclinical models, this will also be a concern for efforts to evaluate the clinical efficacy of anti-Ras therapies. It is likely that Ras mutation status alone will not be sufficient to define the subset of colorectal cancers that will be responsive to inhibitors of Ras signaling, specifically to inhibitors of the Raf and MEK protein kinases. Instead, we hypothesize that other approaches, such as microarray gene profiling, will be needed to determine the subsets of Ras mutation positive colorectal cancers that will be responsive to anti-Raf or anti-MEK therapy. Therefore, the broad goal of this project will be to determine whether a group of patients with colorectal carcinomas that harbor mutated Ras show gene expression profiles that may have clinical relevance in predicting sensitivity to anti-Ras and anti-Raf/MEK therapeutic strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1)
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University of North Carolina Chapel Hill
Chapel Hill
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