BET inhibitors in the treatment of hematologic malignancies: Current insights and future prospects

OncoTargets and Therapy

Volumn 9, Issue , 2016, Pages 5943-5953

  Abedin, Sameem M ^a   Boddy, Craig S ^a   Munshi, Hidayatullah G ^a,b  

^a NORTHWESTERN UNIVERSITY   (United States)

^b JESSE BROWN VA MEDICAL CENTER   (United States)

Author keywords

Leukemia; Lymphoma; Multiple myeloma; Resistance mechanisms; Toxicity

Indexed keywords

4 (4 CHLOROPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETIC ACID TERT BUTYL ESTER; 6 (4 CHLOROPHENYL) N ETHYL 8 METHOXY 1 METHYL 4H [1,2,4]TRIAZOLO[4,3 A][1,4]BENZODIAZEPINE 4 ACETAMIDE; 7 (3,5 DIMETHYL 4 ISOXAZOLYL) 1,3 DIHYDRO 8 METHOXY 1 [1 (2 PYRIDINYL)ETHYL] 2H IMIDAZO[4,5 C]QUINOLIN 2 ONE; ABBV 075; AZACITIDINE; BENDAMUSTINE; BIRABRESIB; BORTEZOMIB; BROMODOMAIN INHIBITOR; CPI 0610; CYTARABINE; DECITABINE; DOXORUBICIN; EVEROLIMUS; FT 1101; IBRUTINIB; IDELALISIB; INCB 054329; INCB 057643; LENALIDOMIDE; MELPHALAN; MYC PROTEIN; PANOBINOSTAT; QUIZARTINIB; RITUXIMAB; ROMIDEPSIN; TEN 010; UNCLASSIFIED DRUG; VINCRISTINE; VORINOSTAT;

ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; ANTIPROLIFERATIVE ACTIVITY; BURKITT LYMPHOMA; BURKITT LYMPHOMA CELL LINE; CANCER COMBINATION CHEMOTHERAPY; CHRONIC LYMPHATIC LEUKEMIA; CHRONIC MYELOID LEUKEMIA; CYTOPENIA; DIARRHEA; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; FATIGUE; GENE MUTATION; GENE OVEREXPRESSION; HEMATOLOGIC MALIGNANCY; HUMAN; HYPERBILIRUBINEMIA; LARGE CELL LYMPHOMA; LEUKEMIA; LYMPHOCYTOMA; LYMPHOMA; MANTLE CELL LYMPHOMA; MARGINAL ZONE LYMPHOMA; MONOTHERAPY; MULTIPLE MYELOMA; MYELODYSPLASTIC SYNDROME; MYELOFIBROSIS; MYELOPROLIFERATIVE NEOPLASM; NAUSEA; NONHUMAN; ONCOGENE C MYC; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIMARY EFFUSION LYMPHOMA; REVIEW; T CELL LYMPHOMA; THROMBOCYTOPENIA; TREATMENT RESPONSE; VOMITING;

EID: 84989325811     PISSN: None     EISSN: 11786930     Source Type: Journal    
DOI: 10.2147/OTT.S100515     Document Type: Review

References (53)

1. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-917.
2. Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067-1073.
3. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108(40):16669-16674.
4. Boi M, Gaudio E, Bonetti P, et al. The BET bromodomain inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res. 2015;21(7):1628-1638.
5. Berthon C, Raffoux E, Thomas X, et al. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 2016;3(4):e186-e195.
6. Amorim S, Stathis A, Gleeson M, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016;3(4):e196-e204.
7. Wang CY, Filippakopoulos P. Beating the odds: BETs in disease. Trends Biochem Sci. 2015;40(8):468-479.
8. Sahai V, Redig AJ, Collier KA, Eckert FD, Munshi HG. Targeting bet bromodomain proteins in solid tumors. Oncotarget. 2016;7(33):53997-54009.
9. Loven J, Hoke HA, Lin CY, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153(2):320-334.
10. Whyte WA, Orlando DA, Hnisz D, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;152(2):307-319.
11. Hnisz D, Abraham BJ, Lee TI, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155(4):934-947.
12. Chapuy B, McKeown MR, Lin CY, et al. Discovery and characterization of super-enhancer associated dependencies in diffuse large B-cell lymphoma. Cancer Cell. 2013;24(6):777-790.
13. Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 1975-2013. Bethesda, MD: National Cancer Institute. Available from: http://seer.cancer.gov/csr/1975_2013/. Accessed June 16, 2016.
14. Rowe JM, Li X, Cassileth PA, et al. Very poor survival of patients with AML who relapse after achieving a first complete remission: the Eastern Cooperative Oncology Group experience. Blood. 2005;106(11):546.
15. Döhner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740-3746.
16. Schlenk RF, Döhner K, Krauter J, et al; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909-1918.
17. Thirman MJ, Gill HJ, Burnett RC, et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N Engl J Med. 1993;329(13):909-914.
18. Dawson MA, Gudgin EJ, Horton SJ, et al. Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia. Leukemia. 2014;28(2):311-320.
19. Falini B, Bolli N, Shan J, et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc + AML. Blood. 2006;107(11):4514-4523.
20. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7(11):823-833.
21. Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478(7370):529-533.
22. Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood. 2010;116(24):5089-5102.
23. Fiskus W, Sharma S, Qi J, et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol Cancer Ther. 2014;13(10):2315-2327.
24. Roll JD, Reuther GW. CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. Cancer Res. 2010;70(19):7347-7352.
25. Ott CJ, Kopp N, Bird L, et al. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012;120(14):2843-2852.
26. Picaud S, Costa DD, Thanasopoulou A, et al. PFI-1 - a highly selective protein interaction inhibitor targeting BET bromodomains. Cancer Res. 2013;73(11):3336-3346.
27. Loosveld M, Castellano R, Gon S, et al. Therapeutic targeting of c-Myc in T-cell acute lymphoblastic leukemia, T-ALL. Oncotarget. 2014;5(10):3168-3172.
28. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116(12):2040-2045.
29. Pfreundschuh M, Kuhnt E, Trümper L, et al; MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12(11):1013-1022.
30. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184-4190.
31. Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33(26):2848-2856.
32. Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011;117(8):2319-2331.
33. Ceribelli M, Kelly PN, Shaffer AL, et al. Blockade of oncogenic IκB kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors. Proc Natl Acad Sci U S A. 2014;111(31):11365-11370.
34. Horn H, Ziepert M, Becher C, et al; German High-Grade Non-Hodgkin Lymphoma Study Group. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121(12):2253-2263.
35. Trabucco SE, Gerstein RM, Evens AM, et al. Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res. 2015;21(1):113-122.
36. Blum KA, Lozanski G, Byrd JC. Adult Burkitt leukemia and lymphoma. Blood. 2004;104(10):3009-3020.
37. Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011;117(1):26-38.
38. Sun B, Shah B, Fiskus W, et al. Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015;126(13):1565-1574.
39. Tolani B, Gopalakrishnan R, Punj V, Matta H, Chaudhary PM. Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene. 2014;33(22):2928-2937.
40. Boi M, Bonetti P, Ponzoni M, et al. The Brd-inhibitor OTX015 shows pre-clinical activity in anaplastic large T-cell lymphoma (ALCL). Blood. 2012;120(21):4872.
41. Larsson CA, Kojima K, Wang Y, et al. BET bromodomain inhibition reduces leukemic burden and prolongs survival in the Eμ-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) independent of TP53 mutation status. Blood. 2013;122(21):876.
42. Mahindra A, Hideshima T, Anderson KC. Multiple myeloma: biology of the disease. Blood Rev. 2010;24 Suppl 1:S5-S11.
43. Ghurye RR, Stewart HJS, Chevassut TJ. Bromodomain inhibition by JQ1 suppresses lipopolysaccharide-stimulated interleukin-6 secretion in multiple myeloma cells. Cytokine. 2015;71(2):415-417.
44. Chaidos A, Caputo V, Gouvedenou K, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014;123(5):697-705.
45. Antin JH, Raley DY. Manual of Stem Cell and Bone Marrow Transplantation. New York, NY: Cambridge University Press; 2009.
46. Sun Y, Wang Y, Toubai T, et al. BET bromodomain inhibition suppresses graft-versus-host disease after allogeneic bone marrow transplantation in mice. Blood. 2015;125(17):2724-2748.
47. Fong CY, Gilan O, Lam EYN, et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature. 2015;525(7570):538-542.
48. Rathert P, Roth M, Neumann T, et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature. 2015;525(7570):543-547.
49. Herrmann H, Blatt K, Shi J, et al. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia (AML). Oncotarget. 2012;3(12):1588-1599.
50. Coudé M-M, Braun T, Berrou J, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015;6(19):17698-17712.
51. Fiskus W, Sharma S, Qi J, et al. Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014;13(5):1142-1154.
52. Moros A, Rodríguez V, Saborit-Villarroya I, et al. Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma. Leukemia. 2014;28(10):2049-2059.
53. Siegel MB, Liu SQ, Davare MA, et al. Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma. Oncotarget. 2015;6(22):18921-18932.