Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies
| Autor: | Olga Tayber, Erik Kupperman, Zhi Li, Joseph B. Bolen, Ping Li, Kristen Bano, Jennifer Terkelsen, Allison Berger, Brian G Van Ness, Michael D. Pickard, Matthew D. Silva, Mary Carsillo, Paul Hales, Michael Fitzgerald, Siegfried Janz, Ozlem Subakan, Daniel P. Bradley, Mark Manfredi, Edmund Lee, Vishala T. Neppalli, Bret Bannerman, Jill Donelan, Raymond W. Liu |
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| Rok vydání: | 2011 |
| Předmět: |
Boron Compounds
Cancer Research Lymphoma B-Cell Cell Glycine Antineoplastic Agents Mice Transgenic Mice SCID Osteolysis Pharmacology Article Bortezomib Mice In vivo Mice Inbred NOD Cell Line Tumor medicine Animals Humans Protease Inhibitors Neoplasms Plasma Cell B cell business.industry Cancer medicine.disease Boronic Acids Xenograft Model Antitumor Assays Lymphoma Mice Inbred C57BL medicine.anatomical_structure Oncology Proteasome Pyrazines Proteasome inhibitor business Proteasome Inhibitors medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(23) |
| ISSN: | 1557-3265 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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