Aurora kinases are a family of serine/threonine (S/T) kinases (Aurora A, B, C) that function predominantly in the mitotic-phase of the cell cycle. All 3 Auroras possess a highly conserved C-terminal kinase domain with a variable length N-terminal extension. These kinases regulate the completion of centrosome separation, bipolar spindle assembly, chromosome segregation and cytokenesis. Aberrant over-expression of Aurora A and B are oncogenic as they over-ride the mitotic and spindle check points leading to aneuploidy and genomic instability. Previously, we utilized small interference RNA (RNAi) techniques to validate Aurora A as an oncogenic target. We then evaluated the lymphoma, leukemia molecular profiling project (LLMPP) gene expression profile of ~100 mantle cell lymphoma (MCL) patients and demonstrated that over-expression of Aurora A and B, as 'signature genes for proliferation', predicts for an inferior overall survival and hence is a poor prognostic factor. Further, we showed that Aurora A is over-expressed in several of human MCL and DLBCL cell lines, Therefore, targeting Aurora with a specific small molecular inhibitor (SMI) might be of therapeutic value in aggressive B-cell non-Hodgkin's lymphomas (NHL). Hence, we utilized a structurebased drug discovery approach to design and synthesize a specific ATP-competitive Aurora SMI (SGI-498). Treatment of MCL and DLBCL cell lines with SGI-498 led to reduced cell viability and apoptosis in the 5- 10|aM IC50 range. Large animal safety studies have been conducted and an IND application is in progress (in collaboration with Supergen). Collectively these data show that Aurora is an excellent oncogenic drug target in aggressive subsets of B-cell NHL. Despite encouraging data in cell lines, there has not been a comprehensive study evaluating the expression of Aurora kinases in fresh tumor specimens of aggressive B-cell NHL nor a clinical test of efficacy in lymphoma patients. Therefore, the hypotheses to be tested in this Project 1 are: (1). Aurora A and B are over-expressed in fresh human aggressive B-cell NHL (mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (TFL)) tissues, (2). Aurora inhibitor SGI-498 is effective in promoting apoptosis in cell culture and tumor regression in a mouse xenograft model(s) of NHL and (3). SGI-498 will be safe and effective in treating patients with relapsed aggressive B-cell NHL in a early Phase clinical trial.
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