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Ref Type Journal Article
PMID (28416490)
Authors Bui MH, Lin X, Albert DH, Li L, Lam LT, Faivre EJ, Warder SE, Huang X, Wilcox D, Donawho CK, Sheppard GS, Wang L, Fidanze S, Pratt JK, Liu D, Hasvold L, Uziel T, Lu X, Kohlhapp F, Fang G, Elmore SW, Rosenberg SH, McDaniel KF, Kati WM, Shen Y
Title Preclinical Characterization of BET Family Bromodomain Inhibitor ABBV-075 Suggests Combination Therapeutic Strategies.
Journal Cancer research
Vol 77
Issue 11
Date 2017 06 01
URL
Abstract Text ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models, representing a variety of hematologic malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell-cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin lymphoma, and multiple myeloma cells. Apoptosis induced by ABBV-075 was mediated in part by modulation of the intrinsic apoptotic pathway, exhibiting synergy with the BCL-2 inhibitor venetoclax in preclinical models of AML. In germinal center diffuse large B-cell lymphoma, BCL-2 levels or venetoclax sensitivity predicted the apoptotic response to ABBV-075 treatment. In vivo combination studies uncovered surprising benefits of low doses of ABBV-075 coupled with bortezomib and azacitidine treatment, despite the lack of in vitro synergy between ABBV-075 and these agents. The in vitro/in vivo activities of ABBV-075 described here may serve as a useful reference to guide the development of ABBV-075 and other BET family inhibitors for cancer therapy. Cancer Res; 77(11); 2976-89. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Mivebresib ABBV-075 BET Inhibitor (Pan) 27 Mivebresib (ABBV-075) is a bromodomain (BET) inhibitor, which may disrupt transcriptional regulation and lead to apaotosis of tumor cells (PMID: 28416490, PMID: 31420359).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown acute myeloid leukemia not applicable Mivebresib Preclinical - Patient cell culture Actionable In a preclinical study, Mivebresib (ABBV-075) induced apoptosis and inhibited growth of acute myeloid leukemia (AML) cell lines and patient-derived cells in culture, and inhibited tumor growth in an AML cell line xenograft model (PMID: 28416490). 28416490
Unknown unknown multiple myeloma not applicable Bortezomib + Mivebresib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Velcade (bortezomib) and Mivebresib (ABBV-075) resulted in increased tumor growth inhibition in a multiple myeloma cell line xenograft model compared to Velcade (bortezomib) alone (PMID: 28416490). 28416490
Unknown unknown multiple myeloma not applicable Azacitidine + Mivebresib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Vidaza (azacitidine) and Mivebresib (ABBV-075) resulted in increased tumor growth inhibition in a multiple myeloma cell line xenograft model compared to either agent alone (PMID: 28416490). 28416490
Unknown unknown acute myeloid leukemia not applicable Mivebresib + Venetoclax Preclinical - Cell line xenograft Actionable In a preclinical study, Mivebresib (ABBV-075) and Venclexta (venetoclax) worked synergistically to decrease viability of a acute myeloid leukemia (AML) cell lines in culture, and the combination resulted in increased tumor growth inhibition in an AML cell line xenograft model compared to either agent alone (PMID: 28416490). 28416490
Unknown unknown acute myeloid leukemia not applicable Azacitidine + Mivebresib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Vidaza (azacitidine) and Mivebresib (ABBV-075) resulted in increased tumor growth inhibition in an acute myeloid leukemia cell line xenograft model compared to either agent alone (PMID: 28416490). 28416490
Unknown unknown acute myeloid leukemia not applicable Bortezomib + Mivebresib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of Velcade (bortezomib) and Mivebresib (ABBV-075) resulted in increased tumor growth inhibition in an acute myeloid leukemia cell line xenograft model compared to Velcade (bortezomib) alone (PMID: 28416490). 28416490