Targeted Therapies; Who Detects the Target?

Editorial Targeted therapies; who detects the target? After decades in which anti-cancer drugs mainly were designed to inhibit tumor cell proliferation or to interfere with DNA integrity in order to induce apop-tosis in a very general way, we recently have been witnessing the development of a new class of anticancer drugs specifically targeted at biological properties of tumor cells. Examples are Imatinib working against the Kit oncogene and Bcr-Abl tyrosine kinase, respectively , Trastuzumab against Her2Neu, and several drugs including Gefitinib and Erlotinib against EGFR [5,6,11]. In addition, drugs targeted against VEGF, SRC and other molecules have been registered or are in development [4,12]. The concept of targeted anti-cancer drug therapies is very appealing and preclini-cal studies in this area have been very promising. Yet, results in some clinical studies have been less exciting than had been expected on the basis of pre-clinical studies [8]. Two factors are relevant in this respect. The first is whether in the tumors of the patients receiving these therapies, the target molecule actually plays a critical role. One approach to determine this is trial and error. Just give the drug to any patient with a tumor type in which some activity of the drug has been reported. This approach has a number of drawbacks. First of all, treating a patient with a drug that has no chance of being effective because it does not match with the biology of that tumor, is a waste of time in which alternative drugs with a higher chance of response could have been administered to the patient. Second, costs of these targeted drugs have a major impact on health-care budgets and hardly justify a trial and error approach [16]. The other approach is prediction of response to therapy, based on demonstrating certain biological characteristics of the target molecule in a given tumor. This frequently implies immunohistochemical analysis of gene expression in tumor tissue samples. This approach has proven to be of value in the case of c-kit and Her2Neu. Yet, standardization issues remain , both in terms of performing as well as interpreting the stainings. In this respect looking at DNA alterations like amplifications seems to be more robust, and FISH actually now is the gold standard for analyzing Her2Neu amplifications. The second factor is whether in addition to the status of the target gene, other major biological tumor characteristics determine clinical behavior in such a way that …