New targeted therapies in gastrointestinal cancers.

Despite surgical, radiotherapeutic, and chemotherapeutic advances, a large proportion of gastrointestinal (GI) cancers remain incurable. An improved understanding of the molecular pathogenesis of cancer has promulgated the development of novel agents designed to target critical pathways involved in cancer development and progression. The crucial role of the epidermal growth factor receptor (EGFR) in tumor proliferation and the overexpression of EGFR in several GI cancers provides the rationale for targeting and interrupting this key signaling network. EGFR blockade through monoclonal antibodies (C225 and ABX-EGF) and tyrosine kinase inhibitors (ZD1839 and OSI-774) has translated into promising evidence of clinical benefit. Ras-mediated signal transduction has been targeted using inhibitors of farnesyl transferase (R115777 and SCH66336) to block the post-translation modification of Ras. Inhibitors of vascular growth factor receptor (bevacizumab and PTK787) and matrix metalloproteinase target the effects of the host environment. Cyclooxygenase-2 inhibitors in colorectal cancer and STI571 in GI stromal tumors represent novel therapies of interest for these specific GI cancers. Evidence suggests that novel agents can be administered alone or in combination with standard therapies with little additional toxicity. The results of ongoing and future research efforts will clarify the optimal use and survival benefit of targeted therapies for patients with GI malignancies.