Abstract
Alisertib, an Aurora A kinase inhibitor, shows efficacy in aggressive B- and T-cell lymphomas.
Major finding: Alisertib, an Aurora A kinase inhibitor, shows efficacy in aggressive B- and T-cell lymphomas.
Clinical Relevance: Response to alisertib is independent of AURKA amplification and Aurora A protein expression.
Impact: Aurora A inhibitors warrant further study in single-agent and combination clinical trials.
Upregulation of the oncogenic mitotic kinase Aurora A (encoded by AURKA) is frequently detected in aggressive non-Hodgkin lymphomas and is correlated with poor prognosis, implicating Aurora A as a potential therapeutic target. In preclinical studies, alisertib, a selective, small-molecule Aurora A kinase inhibitor, induced mitotic arrest and apoptosis in lymphoma cell lines and suppressed tumor growth in a mouse model of diffuse large B-cell lymphoma (DLBCL). To further investigate the therapeutic potential of Aurora A inhibition, Friedberg and colleagues evaluated the safety and efficacy of alisertib in a phase II trial of 48 patients with various subtypes of relapsed or refractory aggressive non-Hodgkin lymphomas. Alisertib was generally well tolerated and several patients continued therapy beyond 1 year; the most common treatment-related grade 3–4 adverse events consisted of cytopenias, stomatitis, and fatigue, and dose reductions were associated with higher trough plasma concentrations of alisertib. Single-agent treatment with alisertib resulted in an overall response rate of 27% (13 of 48 patients), including complete responses in 10% of patients, partial responses in 17% of patients, and stable disease in 33% of patients. Clinical responses were observed across the various subtypes of non-Hodgkin lymphoma in 3 of 21 patients with DLBCL, 3 of 13 patients with mantle-cell lymphoma, 2 of 5 patients with transformed follicular lymphoma, 4 of 8 patients with noncutaneous T-cell lymphoma, and 1 of 1 patient with Burkitt lymphoma. However, this clinical benefit was not correlated with AURKA gene amplification or Aurora A kinase protein expression in tumor samples. These results support additional clinical trials of alisertib, alone or in combination with other therapeutic agents that may synergize with or sensitize tumors to Aurora A inhibition, in aggressive B- and T-cell lymphomas.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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