Abstract 3684: Targeting Aurora kinase in peripheral T-cell non-Hodgkin's lymphomas

Abstract

Abstract Aurora kinases (A and B) are oncogenic serine/threonine (S/T) kinases that play central roles in the mitotic phase of the eukaryotic cell cycle. Over-expression of Auroras during dysregulated cell cycling and their aberrant activation over-rides mitotic and spindle check points leading to anueploidy in many human cancers make Auroras attractive therapeutic targets. Gene expression profiling in mantle cell lymphoma [MCL] have shown the Auroras are over-expressed and is a poor prognostic marker within the ‘proliferative’ signature. PTCL (NOS) are a heterogeneous group of rare non-Hodgkin's lymphomas (NHL) derived from activated CD4+ or CD8+ T cells. PTCL and anaplastic large cell lymphoma (ALCL) both of T-cell phenotype and ALK negative have an aggressive clinical course with an inferior event free and overall survival relative to B-cell NHL counterparts. The biological explanation for the difference is unknown. Patients with PTCL have a poor prognosis due to a very aggressive disease course coupled to a lack of effective therapies. Therefore, the development of novel and effective treatments based on biologically validated targets is urgently needed for this disease. We hypothesized and investigated that (1). Auroras are over-expressed in human PTCL-NOS, (2). Aurora ATP-site small molecule inhibitor (SMI) is effective in inhibiting cell proliferation and promoting apoptosis in cell culture and (3). Aurora SMI will be safe and effective in treating patients with relapsed aggressive T-cell NHL in early phase clinical trials. In this study, we demonstrate that both aurora A and B are highly over-expressed in PTCL patients and cell lines. MLN8237 (alisertib), an ATP-site small molecule inhibitor of Aurora A had potent activity in inhibiting phosphorylation of Aurora A and histone H3 in PTCL cell lines. Cells treated with MLN8237 exhibited endoreduplication confirming the mechanism of action of an Aurora inhibitor. Also, treatment of PTCL cell lines with MLN8237 induced apoptosis in a dose and time dependent manner (flow cytometry and PARP-cleavage) and inhibited cell proliferation with an IC50 < 0.1µM. Preliminary data from a phase II clinical trial using single-agent MLN8237 in patients with relapsed refractory aggressive NHL has demonstrated notable activity with 4 confirmed responses in 6 evaluable PTCL patients. Cytokine profiling on day 1 (pre-treatment) and day 8 (post-treatment) showed a profile consistent with aurora A activity. Together the data suggest inhibition of Auroras offers a promising treatment strategy for patients with aggressive T-cell NHL [Funded by the Lymphoma SPORE, P50 CAB0805501A1]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3684. doi:1538-7445.AM2012-3684