Novel points of attack for targeted cancer therapy

Abstract

New molecular insight reveals novel points of attack for targeted cancer therapy. The recent advances in cancer genomics and novel insight into the complex biology of cancer make the promise of personalized, targeted cancer medicine closer than ever. The massive parallel sequencing endeavours performed by The Cancer Genome Atlas, the International Cancer Genome Consortium and by numerous individual investigators have provided a comprehensive genomic characterization of a wide range of cancers. The joint efforts enabled by the improved sequencing technology have demonstrated that individual cancers comprise mutational repertoires with only a few frequently recurrent driver genes. Thus, the identification of new drug targets and novel drugs have accelerated and renewed the hopes of personalized cancer therapy achieving clinical reality for a wider range of cancers. Together with cost-effective sequencing technology to perform comprehensive mutational profiling of each individual cancer, this provides the basis for a personalized cancer medicine revolution within the next few years. The aim of this MiniReview is to provide an overview of the history and evolution of targeted cancer therapy, exemplified by molecularly targeted drugs successfully implemented in the clinic. Furthermore, we aim to highlight novel molecular targets for therapeutic intervention, as well as the main present challenges including inter- and intratumor heterogeneity and cellular plasticity in addition to the importance of the tumor micro-environment. Many cancer patients already receive some form of tailored therapy, and recent evidence suggests that novel and highly innovative, targeted approaches are on their way into the clinic.

Fig. 1

Targeted cancer therapies directed at targets within the cancer cells or micro-environmental targets. Targeted therapy is currently focused on (A) tumor micro-environmental targets such as (1) angiogenic blood vessels (e.g. Bevacuzimab) and (2) re-education of the immune system (e.g. Ipilimumab), or (B) targets on the cancer cells themselves. Targeting cancer cell signaling pathways include (3) targeting extracellular domains of transmembrane receptors (e.g. Cetuximab and Trastuzumab) or (4) intracellular targets, such as TK domains and downstream signaling (e.g. Imatinib). Furthermore, intracellular targets also comprise nuclear signaling (5 and 6; e.g. SERMs). As highlighted in this figure, alternative biomarkers may either be expressed by cells composing tumor micro-environment or by the tumor cells, and importantly, cancer biomarkers may differ from the target itself.