Abstract B189: The Nedd8-activating enzyme inhibitor MLN4924 combined with rituximab induces additive/synergistic anti-tumor activity in preclinical non-Hodgkin's lymphoma models
| Autor: | Sai M. Pulukuri, Derek Liqiang Tou, Allison Berger, Lilli Petruzzelli, Peter G. Smith, Mark Manfredi, Michael D. Pickard, Tary Traore |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 8:B189-B189 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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= 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. |
| Databáze: | OpenAIRE |
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