TY - JOUR
T1 - Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies
AU - Lee, Edmund C.
AU - Fitzgerald, Michael
AU - Bannerman, Bret
AU - Donelan, Jill
AU - Bano, Kristen
AU - Terkelsen, Jennifer
AU - Bradley, Daniel P.
AU - Subakan, Ozlem
AU - Silva, Matthew D.
AU - Liu, Ray
AU - Pickard, Michael
AU - Li, Zhi
AU - Tayber, Olga
AU - Li, Ping
AU - Hales, Paul
AU - Carsillo, Mary
AU - Neppalli, Vishala T.
AU - Berger, Allison J.
AU - Kupperman, Erik
AU - Manfredi, Mark
AU - Bolen, Joseph B.
AU - Van Ness, Brian
AU - Janz, Siegfried
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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 novoPCMand overall survival. The newly developed DP54-Luc-disseminated model of iMycCa/ 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.
AB - 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 novoPCMand overall survival. The newly developed DP54-Luc-disseminated model of iMycCa/ 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=82555189384&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-0636
DO - 10.1158/1078-0432.CCR-11-0636
M3 - Article
C2 - 21903769
AN - SCOPUS:82555189384
VL - 17
SP - 7313
EP - 7323
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 23
ER -
