Abstract 397: The antitumor activity of the investigational drug MLN9708 in genetically engineered mouse models of plasma cell malignancy

Abstract

Abstract Introduction: The proteasome inhibitor VELCADE® (bortezomib) is an important component of the chemotherapeutic strategy in treating multiple myeloma, a plasma cell malignancy (PCM). While genetically engineered mouse models (GEMMs) of cancer often accurately recapitulate their human disease counterparts, their usage in drug discovery settings has been very limited. Here we describe the antitumor activity of a second generation proteasome inhibitor, the investigational drug MLN9708, in the iMycCα/Bcl-XL GEMMs of PCM, in which neoplastic plasma cell development is driven by enforced expression of the Myc and Bcl-XL transgenes. Materials: MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma; MLN2238 was used for all studies below. We previously demonstrated that double transgenic iMycCα/Bcl-XL (C57BL6/FVB) mice develop de novo PCM with short onset (135 days) and full penetrance (100%). We derived a plasma cell tumor (PCT) cell line, DP54, from the bone marrow of a syngeneic mouse previously inoculated with an iMycCα/Bcl-XL tumor. DP54 PCT cells were stably transfected with the firefly luciferase gene, clonally isolated, and designated as DP54-Luc cells. Methods: Nine-week-old iMycCα/Bcl-XL (C57BL6/FVB) mice were untreated or treated with bortezomib (1.2 mg/kg intravenously [IV] twice weekly [BIW]) or MLN2238 (18 mg/kg IV BIW) for 6 consecutive weeks and monitored for tumor-free survival for an additional 25 weeks. To establish disseminated and intraosseous mouse models of iMycCα/Bcl-XL PCM, freshly dissociated DP54-Luc cells were aseptically injected into the lateral tail veins and the bone marrow space of the upper right tibia, respectively, of immunocompromised mice. Once tumor growth was established, mice were randomized and treated with vehicle (5%HPbCD), bortezomib (0.8 mg/kg IV BIW) or MLN2238 (13 mg/kg IV BIW) for 3-4 consecutive weeks. The doses used represent the maximum tolerated dose for each drug in each mouse strain. Results: In the iMycCα/Bcl-XL GEMM of de novo PCM, treatment with bortezomib or MLN2238 significantly prolonged tumor-free survival (+27 and +36 days, respectively; p<0.0001) and decreased plasma immunoglobulin levels compared to untreated controls. In the models of iMycCα/Bcl-XL PCM, treatment with bortezomib and MLN2238 significantly reduced disease burden as measured by IVIS® bioluminescent imaging. Conclusion: GEMMs of cancer have often been viewed as promising alternatives to traditional subcutaneous xenograft models, yet data to support their wider use in drug discovery settings are sparse. Here we demonstrated that carefully implemented GEMM studies can be integrated as an important part of the drug-discovery paradigm. MLN9708 is currently in clinical development for both hematologic and solid tumor indications. Safety and efficacy have not been established. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 397.