Abstract
Alisertib (MLN8237) is a selective small molecule inhibitor of Aurora A kinase that is being developed in multiple cancer indications as a single agent and in combination with other therapies. A significant amount of research has elucidated a role for Aurora A in orchestrating numerous activities of cells transiting through mitosis and has begun to shed light on potential non-mitotic roles for Aurora A as well. These biological insights laid the foundation for multiple clinical trials evaluating the antitumor activity of alisertib in both solid cancers and heme-lymphatic malignancies. Several key facets of Aurora A biology as well as empirical data collected in experimental systems and early clinical trials have directed the development of alisertib toward certain cancer types, including neuroblastoma, small cell lung cancer, neuroendocrine prostate cancer, atypical teratoid/rhabdoid tumors, and breast cancer among others. In addition, these scientific insights provided the rationale for combining alisertib with other therapies, including microtubule perturbing agents, such as taxanes, EGFR inhibitors, hormonal therapies, platinums, and HDAC inhibitors among others. Here, we link the key aspects of the current clinical development of alisertib to the originating scientific rationale and provide an overview of the alisertib clinical experience to date.
Highlights
Cell CycleTrials and has shown clinical activity across a diversity of cancer types, including solid and hematological cancers in adult and pediatric populations
Alisertib potently inhibited the growth of neuroblastoma cells in vitro and resulted in maintained complete responses in three of seven neuroblastoma xenograft models grown in immunocompromised mice; responses which surpassed the activity of other agents tested in these models [29]
Treatment related adverse events of single-agent alisertib are summarized in Table 1 [25, 26, 41]
Summary
Trials and has shown clinical activity across a diversity of cancer types, including solid and hematological cancers in adult and pediatric populations. Though alisertib displays differential antitumor activity across experimental tumor models and in cancer patients, the biological underpinnings for alisertib sensitivity remain unclear. Multiple hypotheses have been developed based on Aurora A biology and data collected in experimental models that predict which cancers will most likely respond to alisertib as a single agent or in combination with other therapeutic agents. The data supporting some of these concepts is shared
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