Molecular Markers in Gastrointestinal Cancer: Targeted Therapy and Tailored Chemotherapy

Molecular profiling allows us to better understand the regula- tory pathways which drive tumor development, differentiation and growth. Recently, major players in these pathways have been identified as potential targets for anticancer therapy, in- cluding monoclonal antibodies against EGFR (epidermal growth factor receptor) and VEGF (vascular endothelial growth factor) or small molecules against tyrosine kinases, proteasome or cell-cycle dependent kinases. In this issue of ONKOLOGIE, Sutter et al. (1) are describing in detail these novel targets in critical pathways and the potential clinical im- plications for the treatment of gastrointestinal (GI) cancers. Cytotoxic therapy has shown only very modest efficacy but in some cases significant toxicity. Identification of novel targets in GI cancer will be critical for the development of more suc- cessful and less toxic treatment strategies. Molecular profiling is also critical to test for presence of the target in the tumor, and to validate whether the target is inhibited and functionally significant. In the future, molecular technologies will become an essential part of successful drug development in patients with GI cancers. Molecular signatures will help to select pa- tients who will more likely benefit from chemotherapy and allow a better monitoring of efficacy of chemotherapy. We will be able to evaluate efficacy of chemotherapy within a couple of days and not weeks or months by measuring surrogate markers such as tumor DNA in serum or inhibition of the tar- get in buccal mucosa. The goal in administering chemotherapeutics is to develop the ability to predict the outcome of therapy in terms of response and toxicity. Technologies have been developed to allow tumor profiling with measurements of protein expression, gene expression levels and germline polymorphisms of genes involved in the pathways of the target as well as the metabolic pathways of drugs that may predict response and toxicity to particular chemotherapeutics. The chemotherapeutics for which particular markers have been shown to predict outcome include the fluoropyrimidines and platinum compounds (2-4). However, ongoing prospective clinical trials will be critical to