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Aurora kinase inhibitors: identification and preclinical validation of their biomarkers
Patrizia Carpinelli1, Jürgen Moll
1Nerviano Medical Sciences Srl. Viale Pasteur 10, 20014 Nerviano (Mi), Italy.
Abstract:
Aurora kinases are key regulators of mitosis and inhibitors being developed by a wide range of pharmaceutical and biotechnology companies for the treatment of cancer. Tumor cells respond differentially on inhibition of different Aurora kinase family members and these differences have to be considered in the clinical development of small-molecule inhibitors with respect to the chosen indications, the schedules or the selection of appropriate end points and they should also guide the development of biomarkers. Preclinical validation of potential biomarkers for Aurora kinase inhibitors led to a first application in clinical trials, as exemplified for the phosphorylation of histone H3 to follow Aurora-B inhibition. This review discusses the criteria for translation into the clinic and the value of pharmacodynamic biomarkers and their potential, but also their limitations to be used as surrogate markers for clinical end points.
Insights
Aurora kinase inhibitors are promising cancer treatments, but their clinical development requires careful consideration of differential tumor cell responses and biomarker strategies. Pharmacodynamic biomarkers show potential but have limitations as surrogate clinical endpoints.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aurora kinases are critical regulators of cell division (mitosis).
- Numerous pharmaceutical and biotechnology companies are developing Aurora kinase inhibitors for cancer therapy.
- Tumor cells exhibit varied responses to the inhibition of different Aurora kinase family members.
Purpose of the Study:
- To discuss the clinical development criteria for Aurora kinase inhibitors.
- To evaluate the utility and limitations of pharmacodynamic biomarkers.
- To guide the selection of appropriate clinical indications, treatment schedules, and endpoints.
Main Methods:
- Review of preclinical validation of biomarkers for Aurora kinase inhibitors.
- Examination of the translation of biomarkers into clinical trials.
- Case example: phosphorylation of histone H3 as a marker for Aurora-B inhibition.
Main Results:
- Differential tumor cell responses necessitate tailored approaches for Aurora kinase inhibitor development.
- Pharmacodynamic biomarkers are crucial for monitoring drug activity in vivo.
- Biomarker development and validation are essential for guiding clinical trial design.
Conclusions:
- Clinical development of Aurora kinase inhibitors must account for specific tumor biology and drug targets.
- Pharmacodynamic biomarkers are valuable but require careful validation to serve as reliable surrogate markers for clinical outcomes.
