Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models

Abstract

8553 Background: Aurora A kinase is a serine/threonine protein kinase that is essential for the successful transit of cells through mitosis. MLN8237 is a selective small molecule inhibitor of Aurora A kinase that has demonstrated anti-tumor activity in animal models of solid human tumors. In this study we explored the anti-tumor effect of MLN8237 in vivo in pre-clinical models of human Diffuse Large B-cell Lymphoma (DLBCL) both as a single agent and in combination with the anti-CD20 monoclonal antibody Rituximab. Methods: Three human DLBCL models were examined in SCID mice. In two of the models (Ly19 & WSU) the tumor cells expressed a constitutively active luciferase, enabling tumor burden analysis in either a subcutaneous or disseminated setting. The third model was a primary DLBCL recently obtained from a patient. Tumor bearing animals were treated for 21 days with MLN8237 (QD PO dosing at 3–20mg/kg), Rituximab (Q7D IV dosing at 10 mg/kg), or the two agents combined. Tumor burden was measured in the disseminated models as a function of luciferase-induced photon flux, and in the subcutaneous models using vernier calipers. Results: MLN8237 induced anti-tumor activity that was dose-dependent in all three models. In LY19 disseminated model, 3 mg/kg of MLN8237 combined with Rituximab induced synergistic anti-tumor activity (n=2); while 10 mg/kg MLN8237 (dosed QD) combined with Rituximab was additive. Importantly, combining MLN8237 with Rituximab led to complete cures in 100% of the animals. In the WSU model, combining MLN8237(3–10mg/kg) with Rituximab resulted in additive tumor growth inhibition. The mean survival endpoint was significantly longer (p=0.003 and <0.001 respectively) in the combination group when compared to the individual group. In the primary lymphoma model, MLN8237(10–20mg/kg) caused a significant anti-tumor effect during treatment period (TGI = 83–95%). Combining MLN8237 and Rituximab in primary model resulted in additive anti-tumor effect. Conclusions: MLN8237 combined with Rituximab was found to reduce tumor burden in an additive and/or synergistic mechanism in multiple DLBCL tumor models. MLN8237 is currently being tested as a single agent in a phase I clinical trail in patients with DLBCL. [Table: see text]