Abstract B189: The Nedd8-activating enzyme inhibitor MLN4924 combined with rituximab induces additive/synergistic anti-tumor activity in preclinical non-Hodgkin's lymphoma models

Abstract

Abstract MLN4924 is a novel, small molecule inhibitor of Nedd8-activating enzyme (NAE) that is currently in Phase I clinical trials in hematologic malignancies. We have previously described the pre-clinical anti-tumor activity of MLN4924 in human xenograft models of hematological and solid tumors. Rituximab is an anti-CD20 monoclonal antibody that has been established as part of the standard of care for the treatment of non-Hodgkin's lymphoma (NHL). In the present study, we investigated whether a combination of MLN4924 and Rituximab may act in a complementary manner in pre-clinical models of NHL. We utilized models of ABC-like Diffuse Large B-cell Lymphoma (ABC-like DLBCL, OCI-Ly10 cells) dependent on NF- B signaling for survival and Germinal Center B-cell like DLBCL (GCB-like DLBCL, OCI-Ly19 cells) that are not dependent on NF-κB signaling for survival. In vivo administration of MLN4924 to mice bearing xenograft tumors of OCI-Ly10 and OCI-Ly19 resulted in a pharmacodynamic response of NAE pathway inhibition. In both models, a single dose of MLN4924 resulted in a dose-dependent inhibition of NAE and stabilization of Cullin Dependent Ligase substrates including Nrf-2 and pI Bα. MLN4924 induced antitumor activity that was dose-dependent in both models. In the OCI-Ly10 model co-administration of MLN4924 (10 or 3 mg/kg) and Rituximab (0.3 or 1 mg/kg) induced either synergistic or additive anti-tumor activity (P>0.05). The combination of 10 mg/kg MLN4924 and 1 mg/kg Rituximab resulted in 3 partial and 7 complete responses. In the OCI-Ly19-luc disseminated lymphoma model combining MLN4924 (10–30 mg/kg) with Rituximab resulted in additive tumor growth inhibition. The mean survival endpoint was significantly longer (p=<0.01) in the combination group when compared to the single agent group. Importantly, all animals in the MLN4924 (60 mg/kg) and Rituximab (10 mg/kg) combination group were still alive 100 days after treatment ended. All doses and regimens were well tolerated. The results of these studies demonstrate that combination treatment with MLN4924 and Rituximab resulted in additive and/or synergistic reduction in tumor burden in the OCI-Ly10 and OCI-Ly19 models. In addition, these data provide the rationale for future clinical evaluation of MLN4924 in combination with Rituximab in lymphoma. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B189.