Investigational epigenetically targeted drugs in early phase trials for the treatment of haematological malignancies

Expert Opinion on Investigational Drugs

Volumn 23, Issue 10, 2014, Pages 1321-1332

  Okosun, Jessica ^a   Packham, Graham ^b   Fitzgibbon, Jude ^c  

^a QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^b SOUTHAMPTON GENERAL HOSPITAL   (United Kingdom)

^c QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

Bromodomain and extra terminal; DOT1L inhibitor; Enhancer of zeste homolog 2 inhibitor; Epigenetics; Inhibitor; Isocitrate dehydrogenase inhibitor; Leukaemia; Lymphoma

Indexed keywords

2 HYDROXYGLUTARIC ACID; ANTINEOPLASTIC AGENT; DNA METHYLTRANSFERASE 3A; ISOCITRATE DEHYDROGENASE; NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; TRANSCRIPTION FACTOR EZH2; NEW DRUG;

BIOLOGICAL ACTIVITY; CANCER RESEARCH; DEREGULATION; DNA METHYLATION; DNA SEQUENCE; EPIGENETICS; GENETIC DISORDER; HEMATOLOGIC MALIGNANCY; HISTONE ACETYLATION; HISTONE METHYLATION; HISTONE MODIFICATION; HUMAN; LEUKEMIA; LYMPHOMA; PHENOTYPE; REGULATORY MECHANISM; REVIEW; SOMATIC MUTATION; ANIMAL; CLINICAL TRIAL (TOPIC); DISEASE COURSE; DRUG DESIGN; GENETIC EPIGENESIS; GENETICS; MOLECULARLY TARGETED THERAPY; PATHOLOGY;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; DISEASE PROGRESSION; DRUG DESIGN; DRUGS, INVESTIGATIONAL; EPIGENESIS, GENETIC; HUMANS; LEUKEMIA; LYMPHOMA; MOLECULAR TARGETED THERAPY;

EID: 84907044830     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2014.923402     Document Type: Review

References (82)

1. Waddington CH. The epigenotype. Endeavour 1942;1:18-20
2. Conrad H. The basic ideas of biology. In: Waddington CH, editor. Towards a theoretical biology. Edinburgh University Press, Edinburgh, Scotland, 1968. p. 1-32
3. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev 2009;23(7):781-3
4. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010;31(1):27-36
5. Allis CD, Berger SL, Cote J, et al. New nomenclature for chromatin-modifying enzymes. Cell 2007;131(4):633-6
6. Kouzarides T. Chromatin modifications and their function. Cell 2007;128(4):693-705
7. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010;363(25):2424-33
8. Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human leukemia. Oncogene 2010;29(25):3723-31
9. Yan XJ, Xu J, Gu ZH, et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 2011;43(4):309-15
10. Grossmann V, Haferlach C, Weissmann S, et al. The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. Genes Chromosomes Cancer 2013;52(4):410-22
11. Neumann M, Heesch S, Schlee C, et al. Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood 2013;121(23):4749-52
12. Marcucci G, Metzeler KH, Schwind S, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol 2012;30(7):742-50
13. Thol F, Damm F, Lüdeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011;29(21):2889-96
14. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360(22):2289-301
15. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009;361(11):1058-66
16. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366(12):1079-89
17. Shen Y, Zhu YM, Fan X, et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood 2011;118(20):5593-603
18. Ito S, D'Alessio AC, Taranova OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010;466(7310):1129-33
19. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009;324(5929):930-5
20. Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010;468(7325):839-43
21. Konstandin N, Bultmann S, Szwagierczak A, et al. Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia. Leukemia 2011;25(10):1649-52
22. Metzeler KH, Maharry K, Radmacher MD, et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2011;29(10):1373-81
23. Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010;28(14):2348-55
24. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010;17(3):225-34
25. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010;18(6):553-67
26. Network CGAR. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368(22):2059-74
27. Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 2009;114(12):2489-96
28. Muntean AG, Hess JL. The pathogenesis of mixed-lineage leukemia. Annu Rev Pathol 2012;7:283-301
29. Tamai H, Inokuchi K. 11q23/MLL acute leukemia: update of clinical aspects. J Clin Exp Hematop 2010;50(2):91-8
30. Meyer C, Kowarz E, Hofmann J, et al. New insights to the MLL recombinome of acute leukemias. Leukemia 2009;23(8):1490-9
31. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 2007;7(11):823-33
32. Krivtsov AV, Feng Z, Lemieux ME, et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 2008;14(5):355-68
33. Okada Y, Feng Q, Lin Y, et al. hDOT1L links histone methylation to leukemogenesis. Cell 2005;121(2):167-78
34. Lohr JG, Stojanov P, Lawrence MS, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci USA 2012;109(10):3879-84
35. Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 2011;476(7360):298-303
36. Okosun J, Bödör C, Wang J, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014;46(2):176-81
37. Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 2011;43(9):830-7
38. Glaser S, Schaft J, Lubitz S, et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development 2006;133(8):1423-32
39. Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011;471(7337):189-95
40. Kirmizis A, Bartley SM, Kuzmichev A, et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev 2004;18(13):1592-605
41. Viré E, Brenner C, Deplus R, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006;439(7078):871-4
42. Bödör C, Grossmann V, Popov N, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood 2013;122(18):3165-8
43. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010;42(2):181-5
44. Majer CR, Jin L, Scott MP, et al. A687V EZH2 is a gain-of-function mutation found in lymphoma patients. FEBS Lett 2012;586(19):3448-51
45. McCabe MT, Graves AP, Ganji G, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci USA 2012;109(8):2989-94
46. Ryan RJ, Nitta M, Borger D, et al. EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas. PLoS One 2011;6(12):e28585
47. Sneeringer CJ, Scott MP, Kuntz KW, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci USA 2010;107(49):20980-5
48. Yap DB, Chu J, Berg T, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 2011;117(8):2451-9
49. Velichutina I, Shaknovich R, Geng H, et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 2010;116(24):5247-55
50. Béguelin W, Popovic R, Teater M, et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 2013;23(5):677-92
51. Caganova M, Carrisi C, Varano G, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest 2013;123(12):5009-22
52. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010;42(8):722-6
53. Nikoloski G, Langemeijer SM, Kuiper RP, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet 2010;42(8):665-7
54. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10(3):223-32
55. Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012;30(21):2670-7
56. Mann BS, Johnson JR, Cohen MH, et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007;12(10):1247-52
57. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010;28(29):4485-91
58. Muntean AG, Tan J, Sitwala K, et al. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell 2010;17(6):609-21
59. Bernt KM, Zhu N, Sinha AU, et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 2011;20(1):66-78
60. Daigle SR, Olhava EJ, Therkelsen CA, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 2011;20(1):53-65
61. Daigle SR, Olhava EJ, Therkelsen CA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 2013;122(6):1017-25
62. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of a-ketoglutarate-dependent dioxygenases. Cancer Cell 2011;19(1):17-30
63. Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 2013;122(16):2877-87
64. Chen C, Liu Y, Lu C, et al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev 2013;27(18):1974-85
65. Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 2013;340(6132):626-30
66. Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013;340(6132):622-6
67. Yen K, Wang F, Travins J, et al. AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model. Blood 2013;122(21):abstract 240
68. Tan J, Yang X, Zhuang L, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 2007;21(9):1050-63
69. Knutson SK, Wigle TJ, Warholic NM, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 2012;8(11):890-6
70. McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012;492(7427):108-12
71. Knutson SK, Kawano S, Minoshima Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2 mutant non-Hodgkin lymphoma. Mol Cancer Ther 2014. [Epub ahead of print]
72. Gyuris A, Donovan DJ, Seymour KA, et al. The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis. Biochim Biophys Acta 2009;1789(5):413-21
73. Houzelstein D, Bullock SL, Lynch DE, et al. Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4. Mol Cell Biol 2002;22(11):3794-802
74. French CA. Pathogenesis of NUT midline carcinoma. Annu Rev Pathol 2012;7:247-65
75. 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
76. 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):529-33
77. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146(6):904-17
78. Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature 2010;468(7327):1067-73
79. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA 2011;108(40):16669-74
80. 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):2843-52
81. Wyspiańska BS, Bannister AJ, Barbieri I, et al. BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms. Leukemia 2014;28(1):88-97
82. Clozel T, Yang S, Elstrom RL, et al. Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov 2013;3(9):1002-19