Biomarkers in drug development

Abstract

Due to the increasing understanding of the mechanisms relevant to the genesis of cancer, we are experiencing a transition from diseaseto target-oriented therapy. Thus the challenge of bringing new therapeutics to clinical application and registration now focuses on the molecular target expressed by the malignant cell rather than treatment of the histopathological entity itself. The new concepts, however, bring along major problems for clinical drug development. One major issue is the limited availability of predictive in vitro models on the one hand, and the need to perform early clinical trials usually in heavily pretreated patients with a considerable tumor load on the other. In the new era of cancer treatment, instead of applying the concept of maximum tolerated dose (MTD) as does cytotoxic drug therapy, we must think in terms of the optimal biologically active dose (OBAD) and the maximum tolerated economic cost. Only administration of molecularly targeted drugs at OBAD can demonstrate their optimum therapeutic efficacy. Biomarkers could play important roles in disease diagnosis and in the identification of patient populations that could benefit from targeted therapy. They also serve as markers of drug efficacy and could be used to monitor treatment effectiveness, drug toxicity and development of resistance. Moreover, some biomarkers appear to be surrogates for clinical benefit; as such, they have the potential to serve as endpoints in clinical trials. To use biomarkers to maximum advantage, several scientific hurdles must be surmounted. For example, a need exists to differentiate molecular and therapeutic targets, determine which targets to block to achieve tumor control, overcome resistance mechanisms and identify patients who need treatment and are potential responders.