Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies.

Abstract

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 iMyc(Cα)/Bcl-X(L) GEM model was used to assess their effects on de novo PCM and overall survival. The newly developed DP54-Luc-disseminated model of iMyc(Cα)/Bcl-X(L) 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 iMyc(Cα)/Bcl-X(L) 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.

• Authors: Edmund C Lee, Michael Fitzgerald, Bret Bannerman, Jill Donelan, Kristen Bano, Jennifer Terkelsen, Daniel P Bradley, Ozlem Subakan, Matthew D Silva, Ray Liu, Michael Pickard, Zhi Li, Olga Tayber, Ping Li, Paul Hales, Mary Carsillo, Vishala T Neppalli, Allison J Berger, Erik Kupperman, Mark Manfredi, Joseph B Bolen, Brian Van Ness, Siegfried Janz
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 23 Pg. 7313-23 (Dec 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21903769 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antineoplastic Agents
• Boron Compounds
• Boronic Acids
• Protease Inhibitors
• Proteasome Inhibitors
• Pyrazines
• Bortezomib
• ixazomib
• Glycine

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Boron Compounds (administration & dosage, pharmacokinetics, pharmacology)
• Boronic Acids (pharmacokinetics, pharmacology)
• Bortezomib
• Cell Line, Tumor
• Glycine (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
• Humans
• Lymphoma, B-Cell (drug therapy, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Mice, Transgenic
• Neoplasms, Plasma Cell (drug therapy, metabolism)
• Osteolysis (drug therapy, etiology)
• Protease Inhibitors (pharmacology)
• Proteasome Inhibitors
• Pyrazines (pharmacokinetics, pharmacology)
• Xenograft Model Antitumor Assays