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Tarantelli C, Bernasconi E, Gaudio E, et al. BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance. ESMO Open. 2018;3(6):e000387doi: 10.1136/esmoopen-2018-000387.
Tarantelli, C., Bernasconi, E., Gaudio, E., Cascione, L., Restelli, V., Arribas, A. J., Spriano, F., Rinaldi, A., Mensah, A. A., Kwee, I., Ponzoni, M., Zucca, E., Carrassa, L., Riveiro, M. E., Rezai, K., Stathis, A., Cvitkovic, E., & Bertoni, F. (2018). BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance. ESMO open, 3(6), e000387. https://doi.org/10.1136/esmoopen-2018-000387
Tarantelli, Chiara, et al. "BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance." ESMO open vol. 3,6 (2018): e000387. doi: https://doi.org/10.1136/esmoopen-2018-000387
Tarantelli C, Bernasconi E, Gaudio E, Cascione L, Restelli V, Arribas AJ, Spriano F, Rinaldi A, Mensah AA, Kwee I, Ponzoni M, Zucca E, Carrassa L, Riveiro ME, Rezai K, Stathis A, Cvitkovic E, Bertoni F. BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance. ESMO Open. 2018 Sep 26;3(6):e000387. doi: 10.1136/esmoopen-2018-000387. eCollection 2018. PMID: 30305939; PMCID: PMC6173228.
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ESMO Open. 2018 Sep 26;3(6):e000387. doi: 10.1136/esmoopen-2018-000387. eCollection 2018.

BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance.

ESMO open

Chiara Tarantelli, Elena Bernasconi, Eugenio Gaudio, Luciano Cascione, Valentina Restelli, Alberto Jesus Arribas, Filippo Spriano, Andrea Rinaldi, Afua Adjeiwaa Mensah, Ivo Kwee, Maurilio Ponzoni, Emanuele Zucca, Laura Carrassa, Maria E Riveiro, Keyvan Rezai, Anastasios Stathis, Esteban Cvitkovic, Francesco Bertoni

Affiliations

  1. Università della Svizzera italiana (USI), Institute of Oncology Research (IOR), Bellinzona, Switzerland.
  2. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
  3. IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
  4. Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.
  5. Department of Onco-Haematology, Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy.
  6. IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  7. OTD Oncology, Therapeutic Development, Clichy, France.
  8. Institut Curie, Hôpital René Huguenin, Saint-Cloud, France.
  9. OncoEthix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp, and Merck & Co., Inc, Kenilworth, New Jersey, USA.

PMID: 30305939 PMCID: PMC6173228 DOI: 10.1136/esmoopen-2018-000387

Abstract

BACKGROUND: The outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.

MATERIALS AND METHODS: The activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.

RESULTS: Birabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.

CONCLUSION: Our data provide the rationale to evaluate birabresib in patients affected by MCL.

Keywords: BET bromodomain; MYC; epigenetics; lymphoma

Conflict of interest statement

Competing interests: Francesco Bertoni and Anastasios Stathis have received institutional research funds from Oncology Therapeutic Development. Maria E. Riveiro was an employee of Oncology Therapeutic

References

  1. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 - PubMed
  2. Oncotarget. 2015 Nov 10;6(35):37229-40 - PubMed
  3. Oncotarget. 2015 Feb 20;6(5):3394-408 - PubMed
  4. Clin Cancer Res. 2018 Jan 1;24(1):120-129 - PubMed
  5. Nature. 2013 Oct 17;502(7471):333-339 - PubMed
  6. Blood. 2015 Jan 1;125(1):48-55 - PubMed
  7. Blood. 2013 Sep 26;122(13):2233-41 - PubMed
  8. Lancet Haematol. 2016 Apr;3(4):e196-204 - PubMed
  9. Mol Cancer Ther. 2016 Nov;15(11):2563-2574 - PubMed
  10. Nat Med. 2014 Jan;20(1):87-92 - PubMed
  11. Br J Haematol. 2017 Sep;178(6):936-948 - PubMed
  12. Leukemia. 2014 Oct;28(10):2049-59 - PubMed
  13. Blood. 2015 Sep 24;126(13):1565-74 - PubMed
  14. Ann Oncol. 2017 Jul 1;28(suppl_4):iv62-iv71 - PubMed
  15. Leukemia. 2018 Feb;32(2):343-352 - PubMed
  16. Blood. 2014 May 8;123(19):2988-96 - PubMed
  17. Stat Appl Genet Mol Biol. 2004;3:Article3 - PubMed
  18. Cancer Cell. 2003 Feb;3(2):185-97 - PubMed
  19. Br J Haematol. 2018 Jul;182(1):46-62 - PubMed
  20. Biostatistics. 2007 Jan;8(1):118-27 - PubMed
  21. Clin Cancer Res. 2015 Apr 1;21(7):1628-38 - PubMed
  22. J Clin Oncol. 2016 Apr 10;34(11):1256-69 - PubMed
  23. Hematol Oncol. 2017 Mar;35(1):79-86 - PubMed
  24. Leuk Lymphoma. 2008 Nov;49(11):2059-80 - PubMed
  25. Ann Oncol. 2016 Jun;27(6):1123-8 - PubMed
  26. Oncogene. 2016 Sep 8;35(36):4689-97 - PubMed
  27. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11365-70 - PubMed
  28. Cancer Cell. 2012 Jun 12;21(6):723-37 - PubMed
  29. Cancer Discov. 2018 Jan;8(1):24-36 - PubMed
  30. Oncotarget. 2016 Sep 6;7(36):58142-58147 - PubMed
  31. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18250-5 - PubMed
  32. Clin Cancer Res. 2015 Jan 1;21(1):113-22 - PubMed
  33. Cancer Cell. 2013 Dec 9;24(6):777-90 - PubMed
  34. Oncogene. 2018 Jul;37(28):3763-3777 - PubMed
  35. Immunol Rev. 2006 Apr;210:67-85 - PubMed

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