PMID- 33999145
OWN - NLM
STAT- MEDLINE
DCOM- 20210531
LR  - 20210925
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 5
IP  - 10
DP  - 2021 May 25
TI  - Study of the antilymphoma activity of pracinostat reveals different sensitivities 
      of DLBCL cells to HDAC inhibitors.
PG  - 2467-2480
LID - 10.1182/bloodadvances.2020003566 [doi]
AB  - Histone deacetylase inhibitors (HDACis) are antitumor agents with distinct 
      efficacy in hematologic tumors. Pracinostat is a pan-HDACi with promising early 
      clinical activity. However, similar to other HDACis, its activity as a single 
      agent is limited. Diffuse large B-cell lymphoma (DLBCL) includes distinct 
      molecular subsets or metabolically defined subtypes that rely in different ways 
      on the B-cell receptor signaling pathway, oxidative phosphorylation, and 
      glycolysis for their survival. The antitumor activity of pracinostat has not been 
      determined in lymphomas. We performed preclinical in vitro activity screening of 
      60 lymphoma cell lines that included 25 DLBCLs. DLBCL cells belonging to distinct 
      metabolic subtypes were treated with HDACis for 6 hours or 14 days followed by 
      transcriptional profiling. DLBCL xenograft models enabled assessment of the in 
      vivo antilymphoma activity of pracinostat. Combination treatments with 
      pracinostat plus 10 other antilymphoma agents were performed. Western blot was 
      used to assess acetylation levels of histone and nonhistone proteins after HDACi 
      treatment. Robust antiproliferative activity was observed across all lymphoma 
      histotypes represented. Focusing on DLBCL, we identified a low-sensitivity subset 
      that almost exclusively consists of the oxidative phosphorylation (OxPhos)-DLBCL 
      metabolic subtype. OxPhos-DLBCL cells also showed poorer sensitivity to other 
      HDACis, including vorinostat. Transcriptomic analysis revealed fewer modulated 
      transcripts but an enrichment of antioxidant pathway genes after HDACi treatment 
      of OxPhos-DLBCLs compared with high-sensitivity B-cell receptor (BCR)-DLBCLs. 
      Pharmacologic inhibition of antioxidant production rescued sensitivity of 
      OxPhos-DLBCLs to pracinostat whereas BCR-DLBCLs were unaffected. Our study 
      provides novel insights into the antilymphoma activity of pracinostat and 
      identifies a differential response of DLBCL metabolic subtypes to HDACis.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Mensah, Afua Adjeiwaa
AU  - Mensah AA
AUID- ORCID: 0000-0001-8113-3689
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Spriano, Filippo
AU  - Spriano F
AUID- ORCID: 0000-0002-8615-1568
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Sartori, Giulio
AU  - Sartori G
AUID- ORCID: 0000-0001-6704-9755
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Priebe, Valdemar
AU  - Priebe V
AUID- ORCID: 0000-0002-8763-0026
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Cascione, Luciano
AU  - Cascione L
AUID- ORCID: 0000-0002-4606-0637
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
AD  - Swiss Institute of Bioinformatics, Lausanne, Switzerland.
FAU - Gaudio, Eugenio
AU  - Gaudio E
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Tarantelli, Chiara
AU  - Tarantelli C
AUID- ORCID: 0000-0002-4394-7742
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Civanelli, Elisa
AU  - Civanelli E
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Aresu, Luca
AU  - Aresu L
AUID- ORCID: 0000-0002-7893-1740
AD  - Department of Veterinary Science, University of Turin, Grugliasco, Turin, Italy.
FAU - Rinaldi, Andrea
AU  - Rinaldi A
AUID- ORCID: 0000-0003-3234-0563
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
FAU - Damia, Giovanna
AU  - Damia G
AUID- ORCID: 0000-0001-9749-434X
AD  - Laboratory of Molecular Pharmacology, Department of Oncology, IRCCS-Istituto di 
      Ricerche Farmacologiche "Mario Negri," Milan, Italy.
FAU - Lovati, Emanuela
AU  - Lovati E
AD  - Helsinn Healthcare, Lugano, Switzerland.
FAU - Zucca, Emanuele
AU  - Zucca E
AUID- ORCID: 0000-0002-5522-6109
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
AD  - Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and.
FAU - Stathis, Anastasios
AU  - Stathis A
AD  - Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and.
AD  - Faculty of Biomedical Sciences, USI, Lugano, Switzerland.
FAU - Pietra, Claudio
AU  - Pietra C
AD  - Helsinn Healthcare, Lugano, Switzerland.
FAU - Bertoni, Francesco
AU  - Bertoni F
AUID- ORCID: 0000-0001-5637-8983
AD  - Institute of Oncology Research, Faculty of Biomedical Sciences, Universita della 
      Svizzera Italiana (USI), Bellinzona, Switzerland.
AD  - Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; and.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzimidazoles)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (SB939 compound)
SB  - IM
MH  - *Antineoplastic Agents/therapeutic use
MH  - Benzimidazoles/therapeutic use
MH  - Histone Deacetylase Inhibitors/pharmacology/therapeutic use
MH  - Humans
MH  - *Lymphoma, Large B-Cell, Diffuse/drug therapy/genetics
PMC - PMC8152508
COIS- Conflict-of-interest disclosure: E.L. is employed by Helsinn Healthcare. C.P. is 
      a past employee of Helsinn Healthcare. E.Z. received institutional research 
      funding from Celgene, Roche, and Janssen, advisory board fees from Celgene, 
      Roche, Mei Pharma, AstraZeneca, and Celltrion Healthcare, and travel grants from 
      AbbVie and Gilead, and provided expert statements to Gilead, Bristol Myers 
      Squibb, and MSD. A.S. received institutional research funds from Bayer, 
      ImmunoGen, Merck, Pfizer, Novartis, Roche, MEI Pharma, and ADC Therapeutics, and 
      travel grants from AbbVie and PharmaMar. F.B. received institutional research 
      funding from Acerta, ADC Therapeutics, Bayer AG, Cellestia, CTI Life Sciences, 
      EMD Serono, Helsinn Healthcare, ImmunoGen, Menarini Ricerche, NEOMED Therapeutics 
      1, Nordic Nanovector ASA, Oncology Therapeutic Development, and PIQUR 
      Therapeutics AG, and consultant fees from Helsinn Healthcare and Menarini 
      Ricerche, provided expert statements to HTG, and received travel grants from 
      Amgen, Astra Zeneca, Jazz Pharmaceuticals, and PIQUR Therapeutics AG. The 
      remaining authors declare no competing financial interests.
EDAT- 2021/05/18 06:00
MHDA- 2021/06/01 06:00
PMCR- 2021/05/17
CRDT- 2021/05/17 12:38
PHST- 2020/10/08 00:00 [received]
PHST- 2021/03/15 00:00 [accepted]
PHST- 2021/05/17 12:38 [entrez]
PHST- 2021/05/18 06:00 [pubmed]
PHST- 2021/06/01 06:00 [medline]
PHST- 2021/05/17 00:00 [pmc-release]
AID - S2473-9529(21)00314-1 [pii]
AID - 2020/ADV2020003566 [pii]
AID - 10.1182/bloodadvances.2020003566 [doi]
PST - ppublish
SO  - Blood Adv. 2021 May 25;5(10):2467-2480. doi: 10.1182/bloodadvances.2020003566.