The unpredictable Northern light: The rise and fall of the aurora kinase inhibitors?

In this issue, Vormoor et al.1 report on the development of an aurora kinase inhibitor (AT9283) in pediatric relapsed/refractory leukemia. Aurora kinases are serine/threonine kinases involved in cellular proliferation by controlling chromatid segregation, and hence as key regulators of cell division, and are considered a relevant target in pediatric leukemias.2 There are three different classes of aurora kinases, with different functions in cell division as reviewed by Keen and Taylor,3 with aurora kinase A and B being most prominently affected in cancer. More than 10 different aurora kinase inhibitors are currently in clinical development, and preclinical data are reported suggesting synergy with drugs that interfere with microtubules and the mitotic spindle (vincristine) and those that induce DNA damage such as topoisomerase II inhibitors.4,5 A lot of interest was generated in the pediatric oncology community for theMLN8237compound (later namedalisertib),which showed impressive preclinical activity in acute lymphoblastic leukemia (ALL) xenografted mice in the Pediatric Preclinical Testing Program,6 but which subsequently failed during further clinical development due to lackof activity in this patient population.Of interest, alisertib is a selective aurora kinase A inhibitor, and some reported preclinical data suggest that inhibition of aurora kinase B, rather than aurora kinase A, results more effectively in proliferation arrest and apoptosis of pediatric leukemia cells.2 AT9283 is a combined aurora kinase A and B inhibitor and hence its dual inhibitory activity may be more effective than alisertib in ALL. The AT9283 leukemia trial was open for approximately 3 years and closed early due to poor recruitment (only seven patients). Which lessons can be learned from this honest and valuable report by the authors, so that the efforts that it takes to set up such studies are not jeopardized by poor recruitment? With increasing cure rates, the number of patients with relapsed/refractory leukemias available for early clinical trials is diminishing, especially in the pediatric setting. In addition, most