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

Edmund C LEE; Siegfried JANZ; Michael FITZGERALD; Michael PICKARD; ZHI LI; Olga TAYBER; PING LI; Paul HALES; Mary CARSILLO; Vishala T NEPPALLI; Allison J BERGER; Erik KUPPERMAN; Mark MANFREDI; Bret BANNERMAN; Joseph B BOLEN; Brian Van NESS; Jill DONELAN; Kristen BANO; Jennifer TERKELSEN; Daniel P BRADLEY; Ozlem SUBAKAN; Matthew D SILVA; Ray LIU

doi:10.1158/1078-0432.CCR-11-0636

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

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

Edmund C LEE, Siegfried JANZ, Michael FITZGERALD, Michael PICKARD, ZHI LI, Olga TAYBER, PING LI, Paul HALES, Mary CARSILLO, Vishala T NEPPALLI, …

Clinical cancer research, Vol.17(23), pp.7313-7323

2011

DOI: 10.1158/1078-0432.CCR-11-0636

PMCID: PMC3443972

PMID: 21903769

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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 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.

Antineoplastic Agents

Biological and medical sciences

Medical sciences

Pharmacology. Drug treatments

Details

Title: Subtitle: Antitumor Activity of the Investigational Proteasome Inhibitor MLN9708 in Mouse Models of B-cell and Plasma Cell Malignancies
Creators: Edmund C LEE - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Siegfried JANZ - Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, United States
Michael FITZGERALD - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Michael PICKARD - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
ZHI LI - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Olga TAYBER - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
PING LI - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Paul HALES - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Mary CARSILLO - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Vishala T NEPPALLI - Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, United States
Allison J BERGER - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Erik KUPPERMAN - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Mark MANFREDI - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Bret BANNERMAN - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Joseph B BOLEN - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Brian Van NESS - Department of Genetics, Cell Biology & Development, Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota, United States
Jill DONELAN - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Kristen BANO - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Jennifer TERKELSEN - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Daniel P BRADLEY - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Ozlem SUBAKAN - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Matthew D SILVA - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Ray LIU - Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, United States
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.17(23), pp.7313-7323
DOI: 10.1158/1078-0432.CCR-11-0636
PMID: 21903769
PMCID: PMC3443972
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Publisher: American Association for Cancer Research
Language: English
Date published: 2011
Academic Unit: Pathology
Record Identifier: 9984083211002771

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