29 Context, background, aims, and outline of the thesis Context Deregulated HGF/SF-MET signaling has been implicated in many human solid cancers (1). Since MET is mutated, overexpressed (at mRNA and protein level), and orchestrates invasive growth in HNSCC (2-4), it is a target of interest (5, 6). This has led to the development of a plethora of MET targeted therapies, which effectivities are under investigation (7, 8). Unfortunately, major survival benefits have not yet been obtained (8, 9). This, together with the high costs that come along with the treatment of cancer patients, hinders the use of MET-based targeted therapies in clinical practice (10, 11). An explanation for the absence of clinical benefit of MET targeted therapies may be found in the absence of suitable companion diagnostics (CDx) (9), defined as “a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product” (12). The development of CDx for targeted therapies directed against MET is complicated due to several reasons (9). Some have a technical origin, such as the lack of reliable antibodies and optimal scoring methods (7, 9, 13), while other reasons may be due to biology, such as ectodomain shedding (9). Prior to stating the aims and outline of this thesis some methods and biological concepts, which we consider to be essential for grasping the context of the performed work, are introduced. The need for antibody validation Besides their wide use in scientific research laboratories, antibodies also play a crucial role in molecular pathology and clinical chemistry laboratories. This implies that their use in a diagnostic, prognostic, and/or predictive setting can have a direct effect on clinical decision making (14). Unfortunately, it has been described that almost half of commercially available antibodies do not perform as expected with respect to immunohistochemistry/immunocytochemistry (15). Moreover, the validity of antibodies is dependent on the method used. This implies that antibodies should be extensively validated before design and/or interpretation of scientific experiments, scoring systems, diagnostic tests, CDx, and clinical guidelines (14). To accomplish this, antibody validation decision models and the five conceptual pillars of application specific antibody validation have been developed (14, 16, 17). 2
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