Antitumor Activity of the Investigational Proteasome Inhibitor MLN9708 in Mouse Models of B-cell and Plasma Cell Malignancies

Purpose: The clinical success of the first-in-class proteasome inhibitor bortezomib (VELCADE) has validated the proteasome as a therapeutic target for treating human cancers. MLN9708 is an investigational proteasome inhibitor that, compared with bortezomib, has improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies. Here, we focused on evaluating the in vivo activity of MLN2238 (the biologically active form of MLN9708) in a variety of mouse models of hematologic malignancies, including tumor xenograft models derived from a human lymphoma cell line and primary human lymphoma tissue, and genetically engineered mouse (GEM) models of plasma cell malignancies (PCM). Experimental Design: Both cell line–derived OCI-Ly10 and primary human lymphoma–derived PHTX22L xenograft models of diffuse large B-cell lymphoma were used to evaluate the pharmacodynamics and antitumor effects of MLN2238 and bortezomib. The iMycCα/Bcl-XL GEM model was used to assess their effects on de novo PCM and overall survival. The newly developed DP54-Luc–disseminated model of iMycCα/Bcl-XL was used to determine antitumor activity and effects on osteolytic bone disease. Results: MLN2238 has an improved pharmacodynamic profile and antitumor activity compared with bortezomib in both OCI-Ly10 and PHTX22L models. Although both MLN2238 and bortezomib prolonged overall survival, reduced splenomegaly, and attenuated IgG2a levels in the iMycCα/Bcl-XL GEM model, only MLN2238 alleviated osteolytic bone disease in the DP54-Luc model. Conclusions: Our results clearly showed the antitumor activity of MLN2238 in a variety of mouse models of B-cell lymphoma and PCM, supporting its clinical development. MLN9708 is being evaluated in multiple phase I and I/II trials. Clin Cancer Res; 17(23); 7313–23. ©2011 AACR.

[1]  Mark Manfredi,et al.  MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. , 2010, Blood.

[2]  M. Rolfe,et al.  Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. , 2010, Cancer research.

[3]  L. Dick,et al.  Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. , 2010, Drug discovery today.

[4]  L. Staudt,et al.  Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. , 2009, Blood.

[5]  M. Bosland,et al.  Strain-dependent differences in susceptibility to lung cancer in inbred mice exposed to mainstream cigarette smoke. , 2009, Cancer letters.

[6]  D. Kuhn,et al.  Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade , 2008, Clinical Cancer Research.

[7]  Douglas Hanahan,et al.  The origins of oncomice: a history of the first transgenic mice genetically engineered to develop cancer. , 2007, Genes & development.

[8]  K. Laurie,et al.  Cell-specific and efficient expression in mouse and human B cells by a novel hybrid immunoglobulin promoter in a lentiviral vector , 2007, Gene Therapy.

[9]  David A. Tuveson,et al.  Maximizing mouse cancer models , 2007, Nature Reviews Cancer.

[10]  S. Janz,et al.  A transgenic mouse model of plasma cell malignancy shows phenotypic, cytogenetic, and gene expression heterogeneity similar to human multiple myeloma. , 2007, Cancer research.

[11]  I. Fidler,et al.  Murine models to evaluate novel and conventional therapeutic strategies for cancer. , 2007, The American journal of pathology.

[12]  R. Cardiff,et al.  Effects of FVB/NJ and C57Bl/6J strain backgrounds on mammary tumor phenotype in inducible nitric oxide synthase deficient mice , 2007, Transgenic Research.

[13]  M. Rolfe,et al.  Comparison of biochemical and biological effects of ML858 (salinosporamide A) and bortezomib , 2006, Molecular Cancer Therapeutics.

[14]  M. Silva,et al.  Application of Surface Roughness Analysis on Micro–Computed Tomographic Images of Bone Erosion: Examples Using a Rodent Model of Rheumatoid Arthritis , 2006, Molecular imaging.

[15]  David A. Tuveson,et al.  The Use of Targeted Mouse Models for Preclinical Testing of Novel Cancer Therapeutics , 2006, Clinical Cancer Research.

[16]  Mallika Singh,et al.  Using Genetically Engineered Mouse Models of Cancer to Aid Drug Development: An Industry Perspective , 2006, Clinical Cancer Research.

[17]  J. Wade Harper,et al.  Drug discovery in the ubiquitin–proteasome system , 2006, Nature Reviews Drug Discovery.

[18]  E. Sausville,et al.  Contributions of human tumor xenografts to anticancer drug development. , 2006, Cancer research.

[19]  R. Gibbs,et al.  Genomic segmental polymorphisms in inbred mouse strains , 2004, Nature Genetics.

[20]  S. Janz,et al.  Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. , 2004, The Journal of clinical investigation.

[21]  J. Adams.  The development of proteasome inhibitors as anticancer drugs. , 2004, Cancer cell.

[22]  M. Linden,et al.  Targeted overexpression of Bcl-XL in B-lymphoid cells results in lymphoproliferative disease and plasma cell malignancies. , 2004, Blood.

[23]  L. Sistonen,et al.  The ubiquitin‐proteasome pathway , 2004, Annals of medicine.

[24]  J. Adams.  Potential for proteasome inhibition in the treatment of cancer. , 2003, Drug discovery today.

[25]  J. Adams,et al.  Proteasome inhibitors as new anticancer drugs , 2002, Current opinion in oncology.

[26]  T. Jacks,et al.  Cancer Modeling in the Modern Era Progress and Challenges , 2002, Cell.

[27]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[28]  Aaron Ciechanover,et al.  The ubiquitin–proteasome pathway: on protein death and cell life , 1998, The EMBO journal.

[29]  A. Ciechanover,et al.  The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Elisa T. Lee,et al.  Statistical Methods for Survival Data Analysis , 1994, IEEE Transactions on Reliability.

[31]  R. Cardiff,et al.  Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. , 2008, The American journal of pathology.

[32]  Ronald A. DePinho,et al.  Model organisms: The mighty mouse: genetically engineered mouse models in cancer drug development , 2006, Nature Reviews Drug Discovery.