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The Clinical Development of Aurora Kinase Inhibitors in Acute Myeloid Leukemia

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Targeted Therapy of Acute Myeloid Leukemia

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

The Aurora family of serine/threonine kinases is essential for chromosome alignment, segregation, centrosomal maturation, mitotic spindle formation, and cytokinesis during mitosis. Their fundamental role in cell cycle regulation and aberrant expression in a broad range of malignancies prompted the development of small molecules that selectively inhibit their activity. Recent studies have revealed new insights into the cellular effects of Aurora kinase inhibition in the treatment of acute myeloid leukemia (AML). Moreover, early-phase clinical studies on AML have shown that these agents have therapeutic efficacy both alone and in combination with chemotherapy.

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Authors and Affiliations

  1. Institute for Drug Development, Cancer Therapy, and Research Center, University of Texas, Health Science Center, Hematology Clinic—Cancer Therapy & Research Center, 78229, San Antonio, TX, USA

    Kevin R. Kelly M.D.

  2. Department of Haematology, Barts and The London NHS Trust, London, E1 2ES, UK

    Ciara L. Freeman M.D.

  3. HRB Clinical Research Facility, Galway & Trinity College Dublin, National University of Ireland, Geata an Eolais University Road, Galway, Ireland

    Francis J. Giles

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  1. Kevin R. Kelly M.D.
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  2. Ciara L. Freeman M.D.
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  3. Francis J. Giles
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Correspondence to Francis J. Giles .

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Editors and Affiliations

  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

Conclusion

Conclusion

Our understanding of the biology of Aurora kinases, their role in oncogenesis, and their suitability as anticancer targets has improved considerably over the past 10 years. Despite this, a number of important questions remain to be fully answered. Whether optimal therapeutic efficacy is achieved through the inhibition of Aurora A, Aurora B, or both kinases simultaneously is still unclear and is the subject of continuing research. Ongoing trials may provide new insights regarding whether there are any advantages to selectively targeting individual Aurora isoforms.

There are a large number of kinases in the human genome. Many of the kinase inhibitors in use in the clinic today were originally developed to inhibit a single kinase but their clinical utility has been attributed to the inhibition of other related kinases. It is likely therefore that some of the clinical efficacy observed with the AKIs currently under clinical investigation can be attributed to off-target kinase inhibition. MK-0457, for example, inhibits the activity of Aurora A and B along with BCR-ABL and FLT3. The clinical responses observed with MK-0457 treatment in highly refractory CML patients may be a consequence of off-target inhibition of BCR-ABL. Likewise, KW-2449 is a potent inhibitor of FLT-3 a factor that may account for some of the activity reported with this drug in AML.

It has yet to be determined whether the expression of Aurora A or Aurora B will predict response to treatment with AKIs. Indeed, this has not been clearly shown in clinical studies performed to date. It would appear that AML , a disease frequently characterized by the rapid proliferation of malignant cells appears to be a disease type associated with objective responses across various AKIs. While high Aurora A or B expression may not necessarily predict response, the expression of the oncogene MYC does appear to predict response to Aurora kinase B inhibitors at least in preclinical models (Hook et al. 2012).

As with many other targeted therapies that are in development the optimal use of AKIs may be in combination with currently available anticancer therapies. Indeed, several promising synergisms between AKIs and chemotherapy and radiotherapy have been demonstrated in vitro and in vivo. An attractive strategy is, combine Aurora inhibitors with tubulin-disrupting agents that arrest cells in mitosis, a stage in the cell cycle where Aurora kinases play a critical role. However, other potential combinations have been evaluated clinically and in preclinical models such as combinations with DNA-damaging agents and monoclonal antibodies.

Despite some of the limitations outlined above, a great deal of enthusiasm for further evaluation of AKIs in the clinic remains. Innovative preclinical science is providing rationale for the development of effective combination strategies that are now being evaluated in clinical trials in AML. It is hoped that these concerted efforts in Aurora kinase research will translate into novel anticancer strategies that will ultimately improve outcomes for patients with AML.

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Kelly, K., Freeman, C., Giles, F. (2015). The Clinical Development of Aurora Kinase Inhibitors in Acute Myeloid Leukemia. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_20

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