There is no evidence for a dominant driver mechanism and resulting addiction to it, as can be observed in several childhood malignancies and gastrointestinal stromal tumor. Finally, comprehensive analyses have started and are likely to provide molecular subgrouping of HCC. Initial attempts have been made (e.g., by J. Zucman-Rossi and her group), clearly demonstrating the feasibility of the approach.26 Improvement can be expected from further meta-analyses of existing data and novel comprehensive analyses on well-characterized collectives. There is significant evidence that molecular classification reflects functional aspects

and correlates with prognosis. At least some of the subgroups are CH5424802 datasheet likely to be relevant for therapy and predictive diagnostics, as exemplified by IGF-IR26,35 and mTOR-associated signaling.87 What are the consequences for drug development, clinical trials, and molecular (predictive) diagnostics?1, 88 There is certainly sufficient room and need for further (pathway) targeted approaches. Constitutive activation, for example,

by mutation or ligand based stimulation of growth factor signaling pathways, is a common theme most likely relevant in every case of HCC.74 On the other side, many different pathways can be affected, and their functional consequences in regard to proliferation, motility, antiapoptosis, and angiogenesis significantly overlap. Thus, response to specific tyrosine kinase–directed approaches may be limited and can be expected only in subgroups of HCCs, and secondary resistance is likely to occur this website soon, because

there is little if any evidence for a specific pathway addiction in HCC. From a mechanistic point of view, approaches to inhibit tyrosine kinase/growth factor signaling pathways should be as broad as possible and should consider complementary PLEKHB2 and combinatorial settings up front. Identification of patients who may benefit (more) from these approaches requires comprehensive biomarker analyses accompanying the clinical trails. This is state-of-the-art in most other malignancies, but has not been thoroughly respected in HCC, probably due to the fact that HCC is the only relevant tumor entity that does not necessarily require tissue-based diagnosis prior to therapy. Because molecular definition of responsive subgroups is not possible without tissue access, this difference may cause more trial failures than expected or necessary and may turn out to be a negative aspect of HCC in comparison with other tumor entities. The fact that protumorigenic alterations in relevant pathways in HCCs may occur at different (nodal) points may limit the application of specific inhibitors and has to be respected in predictive diagnostic approaches as well as drug and subsequent trial design.88 A question that must always be addressed is the size of the responsive patient collective and whether it justifies the clinical and commercial effort.