velopment as single agent or in combination with chemotherapy or epigenetic therapy LY315920 Varespladib , but none has been approved by the US FDA. Clinical trial data emerging for the most advanced SMIs are promising and it is likely that proof of concept targeting will be achievable, and that AKIs will be part of combination treatment for solid and hematologic malignancies in the future. Important factors that are likely to drive progress for success of AKIs in the clinic are duration of enzyme inhibitory activity, schedule, routes of administration, predictive biomarker , non toxic mechanistic combinations with approved as well other targeted therapies, clinical development pathway, and enrichment of appropriate patient populations. 7.0 Expert Opinion The succesful development and approval of an AKI for anti cancer therapy remains unresolved.
However, we believe that aurora kinases are important anti cancer targets that operate in collaboration with other oncogenes intimately involved in uncontrolled tumor proliferation. Aurora inhibitors appear to have excellent activity in tumors with a high mitotic or proliferative index such as acute myeloid MLN8054 leukemia , blast phase of chronic myeloid leukemia , and certain aggressive B and T cell non Hodgkin lymphomas.150 In acute leukemias, it is likely that off target effects on several distinct oncogenic protein kinases contributes to efficacy, although further research is needed. However, resistance mechanisms are operant and pre clinical identification of these would help design better early phase clinical trials where relevant combinations may be evaluated prior to phase II testing.
A similar situation holds for AKI activity in chronic myeloproliferative diseases where these inhibitors are effective in blocking the T315I gate keeper mutation in BCRABL in CML and JAK 2 mutation in polycythemia vera and essential thrombocytosis in early investigations. In contrast, AKIs as single agents have shown modest clinical activity in soild tumor types. Various chemotherapy combinations are planned and/or ongoing to improve clinical activity of AKIs. One such combination is with microtubule targeting agents that inhibits microtubule function and a defective spindle assembly checkpoint simultaneously thereby enhancing apoptosis. However, despite ongoing apoptosis, some tumor cells may escape due to continuing unchecked proliferation.
Therefore, additional agent will be required that target proliferation most likely in the context of KRAS mutations and/or p53 loss, especially in solid tumor types. In diffuse large B cell lymphoma , several molecular abnormalities have been identified, such as c Myc oncoprotein that enhances cell proliferation by regulating transcription of key cell cycle protein kinases including Aurora A and B. Both aurora kinases are over expressed in c Myc driven B cell lymphomas which are resistant to standard R CHOP chemotherapy. It has been demonstrated that induction of aurora A kinase by c Myc is transcriptional and directly mediated via E boxes, while aurora B kinase is indirectly regulated. Inhibition of aurora A and B kinases with a selective AKI triggered transient mitotic arrest, polyploidization, and apoptosis of c Myc induced lymphomas.
An aurora B kinase mutant resistant to AKI continues to have a phenotype of aurora B kinase activation demonstrating that the primary therapeutic target is aurora B kinase in the context of c Myc mediated proliferation.151,152 Furthermore, apoptosis mediated by aurora kinase inhibition was p53 independent, indicating that pan aurora kinase inhibitors will show Green et al. Page 13 Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript efficacy in treating primary or relapsed malignancies with c Myc involvement and/or loss of p53 function. Expression of c Myc using immunohistochemistry or copy number by fluorescence in situ hybridization could be a usef