The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs.
- Boi M Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Gaudio E Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Bonetti P Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Kwee I Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland. Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
- Bernasconi E Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Tarantelli C Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Rinaldi A Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Testoni M Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Cascione L Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland. IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Ponzoni M Unit of Lymphoid Malignancies, Department of Onco-Haematology, San Raffaele Scientific Institute, Milan, Italy.
- Mensah AA Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
- Stathis A IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Stussi G IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Riveiro ME OTD Oncology Therapeutic Development, Clichy, France.
- Herait P Oncoethix, Lausanne, Switzerland.
- Inghirami G Department of Pathology and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York. Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, New York.
- Cvitkovic E OTD Oncology Therapeutic Development, Clichy, France. Oncoethix, Lausanne, Switzerland.
- Zucca E IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Bertoni F Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland. IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. frbertoni@mac.com.
- 2015-01-28
Published in:
- Clinical cancer research : an official journal of the American Association for Cancer Research. - 2015
Acetanilides
Animals
Antineoplastic Agents
Apoptosis
Blotting, Western
Cell Line, Tumor
Cell Proliferation
Chromatin Immunoprecipitation
Drug Synergism
Heterocyclic Compounds, 3-Ring
Humans
Immunohistochemistry
Lymphoma, B-Cell
Mice
Mice, Inbred NOD
Mice, SCID
Nuclear Proteins
Real-Time Polymerase Chain Reaction
Transcriptome
Xenograft Model Antitumor Assays
English
PURPOSE
In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015.
EXPERIMENTAL DESIGN
We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound.
RESULTS
OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell-like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11.
CONCLUSIONS
Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies.
In cancer cells, the epigenome is often deregulated, and inhibition of the bromodomain and extra-terminal (BET) family of bromodomain-containing proteins is a novel epigenetic therapeutic approach. Preliminary results of an ongoing phase I trial have reported promising activity and tolerability with the new BET bromodomain inhibitor OTX015.
EXPERIMENTAL DESIGN
We assessed the preclinical activity of OTX015 as single agent and in combination in mature B-cell lymphoma models and performed in vitro and in vivo experiments to identify the mechanism of action and the genetic features associated with sensitivity to the compound.
RESULTS
OTX015 showed antiproliferative activity in a large panel of cell lines derived from mature B-cell lymphoid tumors with median IC50 of 240 nmol/L, without significant differences among the different histotypes. In vitro and in vivo experiments showed that OTX015 targeted NFKB/TLR/JAK/STAT signaling pathways, MYC- and E2F1-regulated genes, cell-cycle regulation, and chromatin structure. OTX015 presented in vitro synergism with several anticancer agents, especially with mTOR and BTK inhibitors. Gene expression signatures associated with different degrees of sensitivity to OTX015 were identified. Although OTX015 was mostly cytostatic, the compound induced apoptosis in a genetically defined subgroup of cells, derived from activated B-cell-like diffuse large B-cell lymphoma, bearing wtTP53, mutations in MYD88, and CD79B or CARD11.
CONCLUSIONS
Together with the data coming from the ongoing phase I study, the in vitro and in vivo data presented here provide the basis for further clinical investigation of OTX015 as single agent and in combination therapies.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1158/1078-0432.CCR-14-1561
- PMID 25623213
- Persistent URL
- https://susi.usi.ch/global/documents/19692
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