Target Validation and Biomarker Identification in Oncology
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LEADING ARTICLE
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Target Validation and Biomarker Identification in Oncology The Example of Aurora Kinases ¨ Riccardo Colombo and Jurgen Moll Nerviano Medical Sciences Srl, Nerviano, Italy
Abstract
The strong link between gene expression of mitotic Aurora kinases and cancer has stimulated a very high interest in developing Aurora kinase inhibitors for cancer therapy. Validation of Aurora kinases as targets, and development of pharmacodynamic biomarkers for inhibitors of Aurora kinases, provides an example of how target validation can help the drug discovery process, and also of how to interpret results depending on the technology used. In this review, we outline the principal tools, concepts, and strategies of target and biomarker validation for Aurora kinases, with emphasis on validation results derived from RNA-interference experiments. These data were essential for the decision to enter the next steps in drug development and for the selection of the appropriate biomarkers for clinical trials.
1. Targeting Mitosis for Cancer Therapy Tubulin-targeting anti-mitotic therapies such as taxanes (docetaxel, paclitaxel) or vinca alkaloids (vincristine, vinblastine) are effective and widely used in cancer treatment,[1] but they also have limitations related to the role of tubulin in the cytoskeleton of normal cells. Tumor cells are widely regarded as being very sensitive to mitotic arrest, and often undergo cell death in response to agents that perturb the mitotic spindle. Moreover, targeting the mitotic phase of the cell cycle would specifically impact highly proliferating cells, leaving nondividing differentiated cells unaffected. Ideally, normal dividing cells would undergo only a reversible growth arrest, which would be the base for a therapeutic effect that might arise from defects in mitotic checkpoints of cancer cells. Molecular targets that regulate such events, including Aurora kinases, are highly attractive as anticancer targets. 2. Aurora Kinases Aurora kinases represent a family of highly related serine/ threonine kinases that function as key regulators of mitosis. The first Aurora kinase was discovered in yeast in 1993.[2] Since then, Aurora homologs have been identified in higher eukaryotes, and
three Aurora kinases are encoded in the mammalian genome: Aurora-A, Aurora-B, and Aurora-C.[3] Despite their significant sequence homology, these kinases are involved in multiple aspects of mitosis and cell division and have distinct functions and subcellular localizations. • Aurora-A is widely expressed in proliferating tissues, peaking at the G2/M phase of the cell cycle. It localizes to the centrosomes and is also found at the spindle midzone at mitotic exit. Aurora-A primarily functions in centrosome regulation and mitotic spindle formation. • Aurora-B is a component of the chromosomal passenger protein complex and ensures accurate chromosome segregation and cytokinesis. It undergoes a dynamic change in localization during mitosis: it is localized first to
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