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Histone Deacetylase (HDAC) Inhibitors in Recent Clinical Trials for Cancer Therapy

  • Kristina Keller
  • Manfred Jung
Chapter

Abstract

Histone deacetylases are key enzymes of epigenetic regulation and are therefore involved in crucial cellular events like transcription, differentiation, apoptosis and cell division. The deacetylation of many non-histone substrates contributes to these phenomena as well. Thus, these enzymes are an attractive target for anticancer drug development, and first inhibitors are already approved for treatment of cutaneous T-cell lymphoma. About 10–15 inhibitors are currently in clinical trials for a variety of diseases but as single-agent response rates have so far been limited, esp. in solid tumours. There are many open questions, such as the relevance of subtype selectivity in enzyme inhibition, the clinical relevance of non-histone substrates and proper combination regimens. Still, histone deacetylase inhibitors are a promising class of new anticancer agents, and here we review their anticancer properties with a focus on clinical trials from the last 3 years.

Keywords

Partial Response Stable Disease Valproic Acid HDAC Inhibitor Adenoid Cystic Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

bid

Two times daily

CPT-11

Irinotecan

CR

Complete response

CTCL

Cutaneous T-cell lymphoma

DLT

Dose-limiting toxicity

EIAEDs

Enzyme-inducing antiepileptic drugs

FDA

Food and Drug Administration

HDAC

Histone deacetylase

HDACi

Histone deacetylase inhibitor

HI

Haematological improvement

MTD

Maximum tolerated dose

MWF

Monday, Wednesday, Friday

ORR

Overall response rate

OS

Overall survival

PBMC

Peripheral blood mononuclear cell

PFS

Progression free survival

PR

Partial response

qd

Once daily

RP2D

Recommended phase II dose

SD

Stable disease

Notes

Acknowledgments

The authors thank the Deutsche Forschungsgemeinschaft for funding (Ju 295/9-1 within the priority programme SPP1463 Epigenetic regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia; coordinators M. Lübbert, Freiburg, C. Plass, Heidelberg).

References

  1. Arts J, King P, Marien A, Floren W, Belien A, Janssen L, Pilatte I, Roux B, Decrane L, Gilissen R, Hickson I, Vreys V, Cox E, Bol K, Talloen W, Goris I, Andries L, Du Jardin M, Janicot M, Page M, van Emelen K, Angibaud P (2009) JNJ-26481585, a novel “second-generation” oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res 15:6841–6851PubMedCrossRefGoogle Scholar
  2. Atadja P (2009) Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 280:233–241PubMedCrossRefGoogle Scholar
  3. Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O et al (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15:5250–5257PubMedCentralPubMedCrossRefGoogle Scholar
  4. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280:26729–26734PubMedCrossRefGoogle Scholar
  5. Balliet RM, Chen G, Gallagher CJ, Dellinger RW, Sun D, Lazarus P (2009) Characterization of UGTs active against SAHA and association between SAHA glucuronidation activity phenotype with UGT phenotype. Cancer Res 69:2981–2989PubMedCentralPubMedCrossRefGoogle Scholar
  6. Banerji U, van Doorn L, Papadatos-Pastos D, Kristeleit R, Debnam P, Tall M, Stewart A, Raynaud F, Garrett MD, Toal M, Hooftman L, De Bono JS, Verweij J, Eskens FA (2012) A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors. Clin Cancer Res 18:2687–2694PubMedCrossRefGoogle Scholar
  7. Bantscheff M, Hopf C, Savitski MM, Dittmann A, Grandi P, Michon AM, Schlegl J, Abraham Y, Becher I, Bergamini G, Boesche M, Delling M, Dumpelfeld B, Eberhard D, Huthmacher C, Mathieson T, Poeckel D, Reader V, Strunk K, Sweetman G, Kruse U, Neubauer G, Ramsden NG, Drewes G (2011) Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat Biotechnol 29:255–265PubMedCrossRefGoogle Scholar
  8. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784PubMedCrossRefGoogle Scholar
  9. Bonfils C, Kalita A, Dubay M, Siu LL, Carducci MA, Reid G, Martell RE, Besterman JM, Li Z (2008) Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay. Clin Cancer Res 14:3441–3449PubMedCentralPubMedCrossRefGoogle Scholar
  10. Bressi JC, Jennings AJ, Skene R, Wu Y, Melkus R, De Jong R, O’Connell S, Grimshaw CE, Navre M, Gangloff AR (2010) Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett 20:3142–3145PubMedCrossRefGoogle Scholar
  11. Buchwald M, Kramer OH, Heinzel T (2009) HDACi–targets beyond chromatin. Cancer Lett 280:160–167PubMedCrossRefGoogle Scholar
  12. Candelaria M, Herrera A, Labardini J, Gonzalez-Fierro A, Trejo-Becerril C, Taja-Chayeb L, Perez-Cardenas E, de la Cruz-Hernandez E, Arias-Bofill D, Vidal S, Cervera E, Duenas-Gonzalez A (2011) Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial. Ann Hematol 90:379–387PubMedCrossRefGoogle Scholar
  13. Cashen A, Juckett M, Jumonville A, Litzow M, Flynn PJ, Eckardt J, LaPlant B, Laumann K, Erlichman C, DiPersio J (2012) Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS). Ann Hematol 91:33–38PubMedCentralPubMedCrossRefGoogle Scholar
  14. Cervera E, Candelaria M, Lopez-Navarro O, Labardini J, Gonzalez-Fierro A, Taja-Chayeb L, Cortes J, Gordillo-Bastidas D, Duenas-Gonzalez A (2012) Epigenetic therapy with hydralazine and magnesium valproate reverses imatinib resistance in patients with chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk 12:207–212PubMedCrossRefGoogle Scholar
  15. Chinnaiyan P, Chowdhary S, Potthast L, Prabhu A, Tsai YY, Sarcar B, Kahali S, Brem S, Yu HM, Rojiani A, Murtagh R, Pan E (2012) Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma. Neuro Oncol 14:93–100PubMedCentralPubMedCrossRefGoogle Scholar
  16. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840PubMedCrossRefGoogle Scholar
  17. Chung EJ, Lee MJ, Lee S, Trepel JB (2006) Assays for pharmacodynamic analysis of histone deacetylase inhibitors. Expert Opin Drug Metab Toxicol 2:213–230PubMedCrossRefGoogle Scholar
  18. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann P, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan S, Shustov A, Nichols J, Carroll S, Balser J, Balser B, Horwitz S (2012) Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30:631–636PubMedCrossRefGoogle Scholar
  19. Corsetti MT, Salvi F, Perticone S, Baraldi A, De Paoli L, Gatto S, Pietrasanta D, Pini M, Primon V, Zallio F, Tonso A, Alvaro MG, Ciravegna G, Levis A (2011) Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C. Leuk Res 35:991–997PubMedCrossRefGoogle Scholar
  20. David KA, Mongan NP, Smith C, Gudas LJ, Nanus DM (2010) Phase I trial of ATRA-IV and Depakote in patients with advanced solid tumor malignancies. Cancer Biol Ther 9:678–684PubMedCentralPubMedCrossRefGoogle Scholar
  21. Dimicoli S, Jabbour E, Borthakur G, Kadia T, Estrov Z, Yang H, Kelly M, Pierce S, Kantarjian H, Garcia-Manero G (2012) Phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in patients with low or intermediate-1 risk myelodysplastic syndrome. Am J Hematol 87:127–129PubMedCrossRefGoogle Scholar
  22. Dizon DS, Blessing JA, Penson RT, Drake RD, Walker JL, Johnston CM, Disilvestro PA, Fader AN (2012a) A phase II evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 125:367–371PubMedCentralPubMedCrossRefGoogle Scholar
  23. Dizon DS, Damstrup L, Finkler NJ, Lassen U, Celano P, Glasspool R, Crowley E, Lichenstein HS, Knoblach P, Penson RT (2012b) Phase II activity of belinostat (PXD-101), carboplatin, and paclitaxel in women with previously treated ovarian cancer. Int J Gynecol Cancer 22:979–986PubMedCrossRefGoogle Scholar
  24. Doi T, Hamaguchi T, Shirao K, Chin K, Hatake K, Noguchi K, Otsuki T, Mehta A, Ohtsu A (2013) Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial. Int J Clin Oncol 18(1):87–95PubMedCrossRefGoogle Scholar
  25. Dong M, Ning ZQ, Xing PY, Xu JL, Cao HX, Dou GF, Meng ZY, Shi YK, Lu XP, Feng FY (2012) Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas. Cancer Chemother Pharmacol 69:1413–1422PubMedCrossRefGoogle Scholar
  26. Drappatz J, Lee EQ, Hammond S, Grimm SA, Norden AD, Beroukhim R, Gerard M, Schiff D, Chi AS, Batchelor TT, Doherty LM, Ciampa AS, Lafrankie DC, Ruland S, Snodgrass SM, Raizer JJ, Wen PY (2012) Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma. J Neurooncol 107:133–138PubMedCrossRefGoogle Scholar
  27. Dummer R, Beyer M, Hymes K, Epping MT, Bernards R, Steinhoff M, Sterry W, Kerl H, Heath K, Ahern JD, Hardwick JS, Garcia-Vargas J, Baumann K, Rizvi S, Frankel SR, Whittaker SJ, Assaf C (2012) Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition. Leuk Lymphoma 53(8):1501–1508PubMedCrossRefGoogle Scholar
  28. Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, Chiao JH, Reilly JF, Ricker JL, Richon VM, Frankel SR (2007) Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 109:31–39PubMedCentralPubMedCrossRefGoogle Scholar
  29. Duvic M, Dummer R, Becker JC, Poulalhon N, Ortiz Romero P, Grazia Bernengo M (2013) Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer 49:386–394PubMedCrossRefGoogle Scholar
  30. Fakih MG, Fetterly G, Egorin MJ, Muindi JR, Espinoza-Delgado I, Zwiebel JA, Litwin A, Holleran JL, Wang K, Diasio RB (2010) A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors. Clin Cancer Res 16:3786–3794PubMedCentralPubMedCrossRefGoogle Scholar
  31. Fakih MG, Groman A, McMahon J, Wilding G, Muindi JR (2012) A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer. Cancer Chemother Pharmacol 69:743–751PubMedCrossRefGoogle Scholar
  32. Fischer A, Sananbenesi F, Mungenast A, Tsai LH (2010) Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 31:605–617PubMedCrossRefGoogle Scholar
  33. Fournel M, Bonfils C, Hou Y, Yan PT, Trachy-Bourget MC, Kalita A, Liu J, Lu AH, Zhou NZ, Robert MF, Gillespie J, Wang JJ, Ste-Croix H, Rahil J, Lefebvre S, Moradei O, Delorme D, Macleod AR, Besterman JM, Li Z (2008) MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 7:759–768PubMedCrossRefGoogle Scholar
  34. Friday BB, Anderson SK, Buckner J, Yu C, Giannini C, Geoffroy F, Schwerkoske J, Mazurczak M, Gross H, Pajon E, Jaeckle K, Galanis E (2012) Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro Oncol 14:215–221PubMedCentralPubMedCrossRefGoogle Scholar
  35. Fukutomi A, Hatake K, Matsui K, Sakajiri S, Hirashima T, Tanii H, Kobayashi K, Yamamoto N (2012) A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors. Invest New Drugs 30:1096–1106PubMedCrossRefGoogle Scholar
  36. Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M, Nakajima H, Tanaka A, Komatsu Y, Nishino N, Yoshida M, Horinouchi S (2002) FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res 62:4916–4921PubMedGoogle Scholar
  37. Gandia P, Arellano C, Chalret du Rieu Q, Lochon I, Campone M, Pierga JY, Poublanc M, Hennebelle I, Filleron T, Chatelut E, Delord JP (2011) Unexpected high levels of vorinostat when combined with vinorelbine in patients with advanced cancer. Curr Clin Pharmacol 6:274–279PubMedCrossRefGoogle Scholar
  38. Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, Trepel J, Lee MJ, Cao L, Espinoza-Delgado I, Spittler J, Loehrer PJ Sr (2011) Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 29:2052–2059PubMedCentralPubMedCrossRefGoogle Scholar
  39. Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23PubMedCrossRefGoogle Scholar
  40. Gong K, Xie J, Yi H, Li W (2012) CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 443:735–746PubMedCrossRefGoogle Scholar
  41. Gottesfeld JM, Pandolfo M (2009) Development of histone deacetylase inhibitors as therapeutics for neurological disease. Future Neurol 4:775–784PubMedCentralPubMedCrossRefGoogle Scholar
  42. Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20:6969–6978PubMedCentralPubMedCrossRefGoogle Scholar
  43. Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10:32–42PubMedCentralPubMedCrossRefGoogle Scholar
  44. Haigentz M Jr, Kim M, Sarta C, Lin J, Keresztes RS, Culliney B, Gaba AG, Smith RV, Shapiro GI, Chirieac LR, Mariadason JM, Belbin TJ, Greally JM, Wright JJ, Haddad RI (2012) Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. Oral Oncol 48(12):1281–1288PubMedCentralPubMedCrossRefGoogle Scholar
  45. Hainsworth JD, Infante JR, Spigel DR, Arrowsmith ER, Boccia RV, Burris HA (2011) A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Invest 29:451–455PubMedGoogle Scholar
  46. Hideshima T, Bradner JE, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC (2005) Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 102:8567–8572PubMedCentralPubMedCrossRefGoogle Scholar
  47. Hoffmann K, Brosch G, Loidl P, Jung M (1999) A non-isotopic assay for histone deacetylase activity. Nucleic Acids Res 27:2057–2058PubMedCentralPubMedCrossRefGoogle Scholar
  48. Iwamoto FM, Lamborn KR, Kuhn JG, Wen PY, Yung WK, Gilbert MR, Chang SM, Lieberman FS, Prados MD, Fine HA (2011) A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03. Neuro Oncol 13:509–516PubMedCentralPubMedCrossRefGoogle Scholar
  49. Jagannath S, Dimopoulos MA, Lonial S (2010) Combined proteasome and histone deacetylase inhibition: a promising synergy for patients with relapsed/refractory multiple myeloma. Leuk Res 34:1111–1118PubMedCrossRefGoogle Scholar
  50. Jones P (2009) Histone deacetylase inhibitors. In: Sippl W, Jung M (eds) Epigenetic targets in drug discovery. Wiley VCH, New York, pp 185–223CrossRefGoogle Scholar
  51. Jones SF, Bendell JC, Infante JR, Spigel DR, Thompson DS, Yardley DA, Greco FA, Murphy PB, Burris HA 3rd (2011) A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors. Clin Adv Hematol Oncol 9:225–230PubMedGoogle Scholar
  52. Jones SF, Infante JR, Spigel DR, Peacock NW, Thompson DS, Greco FA, McCulloch W, Burris Iii HA (2012) Phase 1 results from a study of romidepsin in combination with gemcitabine in patients with advanced solid tumors. Cancer Invest 30:481–486PubMedCrossRefGoogle Scholar
  53. Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90:85–94PubMedCrossRefGoogle Scholar
  54. Kim GD, Choi YH, Dimtchev A, Jeong SJ, Dritschilo A, Jung M (1999) Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J Biol Chem 274:31127–31130PubMedCrossRefGoogle Scholar
  55. Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V, Matsuoka D, Pulone B, Rotter AJ, Espinoza-Delgado I, Nademanee A, Forman SJ, Gandara D, Newman E (2011) Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 29:1198–1203PubMedCentralPubMedCrossRefGoogle Scholar
  56. Kirschbaum MH, Goldman BH, Zain JM, Cook JR, Rimsza LM, Forman SJ, Fisher RI (2012) A phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: Southwest Oncology Group Study S0517. Leuk Lymphoma 53:259–262PubMedCentralPubMedCrossRefGoogle Scholar
  57. Lane S, Gill D, McMillan NA, Saunders N, Murphy R, Spurr T, Keane C, Fan HM, Mollee P (2012) Valproic acid combined with cytosine arabinoside in elderly patients with acute myeloid leukemia has in vitro but limited clinical activity. Leuk Lymphoma 53:1077–1083PubMedCrossRefGoogle Scholar
  58. Lassen U, Molife LR, Sorensen M, Engelholm SA, Vidal L, Sinha R, Penson RT, Buhl-Jensen P, Crowley E, Tjornelund J, Knoblauch P, de Bono JS (2010) A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours. Br J Cancer 103:12–17PubMedCentralPubMedCrossRefGoogle Scholar
  59. Latham JA, Dent SY (2007) Cross-regulation of histone modifications. Nat Struct Mol Biol 14:1017–1024PubMedCrossRefGoogle Scholar
  60. Leder A, Orkin S, Leder P (1975) Differentiation of erythroleukemic cells in the presence of inhibitors of DNA synthesis. Science 190:893–894PubMedCrossRefGoogle Scholar
  61. Lin RJ, Sternsdorf T, Tini M, Evans RM (2001) Transcriptional regulation in acute promyelocytic leukemia. Oncogene 20:7204–7215PubMedCrossRefGoogle Scholar
  62. Luo J, Su F, Chen D, Shiloh A, Gu W (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408:377–381PubMedCrossRefGoogle Scholar
  63. Ma X, Ezzeldin HH, Diasio RB (2009) Histone deacetylase inhibitors: current status and overview of recent clinical trials. Drugs 69:1911–1934PubMedCrossRefGoogle Scholar
  64. Mateos M, Spencer A, Taylor K, Lonial S, De La Rubia J, Facon T, Bengoudifa B, Hazell K, Bourquelot PM, San-Miguel JF (2010) Phase Ib study of oral panobinostat (LBH589) plus lenalidomide (LEN) plus dexamethasone (DEX) in patients (Pts) with relapsed (Rel) or Rel and refractory (Ref) multiple myeloma (MM). J Clin Oncol (Meeting Abstracts) 28(Suppl):8030Google Scholar
  65. McKinsey TA (2012) Therapeutic potential for HDAC inhibitors in the heart. Annu Rev Pharmacol Toxicol 52:303–319PubMedCrossRefGoogle Scholar
  66. Millward M, Price T, Townsend A, Sweeney C, Spencer A, Sukumaran S, Longenecker A, Lee L, Lay A, Sharma G, Gemmill RM, Drabkin HA, Lloyd GK, Neuteboom ST, McConkey DJ, Palladino MA, Spear MA (2012) Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest New Drugs 30(6):2303–2317PubMedCrossRefGoogle Scholar
  67. Moffat D, Patel S, Day F, Belfield A, Donald A, Rowlands M, Wibawa J, Brotherton D, Stimson L, Clark V, Owen J, Bawden L, Box G, Bone E, Mortenson P, Hardcastle A, van Meurs S, Eccles S, Raynaud F, Aherne W (2010) Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrim idine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor. J Med Chem 53:8663–8678PubMedCrossRefGoogle Scholar
  68. Mohammed TA, Holen KD, Jaskula-Sztul R, Mulkerin D, Lubner SJ, Schelman WR, Eickhoff J, Chen H, Loconte NK (2011) A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. Oncologist 16:835–843PubMedCentralPubMedCrossRefGoogle Scholar
  69. Morita S, Oizumi S, Minami H, Kitagawa K, Komatsu Y, Fujiwara Y, Inada M, Yuki S, Kiyota N, Mitsuma A, Sawaki M, Tanii H, Kimura J, Ando Y (2012) Phase I dose-escalating study of panobinostat (LBH589) Administered intravenously to Japanese patients with advanced solid tumors. Invest New Drugs 30(5):1950–1957PubMedCrossRefGoogle Scholar
  70. Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, Melisko M, Ismail-Khan R, Rugo H, Moasser M, Minton SE (2011) A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer 104:1828–1835PubMedCentralPubMedCrossRefGoogle Scholar
  71. Niesvizky R, Ely S, Mark T, Aggarwal S, Gabrilove JL, Wright JJ, Chen-Kiang S, Sparano JA (2011) Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma. Cancer 117:336–342PubMedCentralPubMedCrossRefGoogle Scholar
  72. Novotny-Diermayr V, Sangthongpitag K, Hu CY, Wu X, Sausgruber N, Yeo P, Greicius G, Pettersson S, Liang AL, Loh YK, Bonday Z, Goh KC, Hentze H, Hart S, Wang H, Ethirajulu K, Wood JM (2010) SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol Cancer Ther 9:642–652PubMedCrossRefGoogle Scholar
  73. Offidani M, Polloni C, Cavallo F, Marina Liberati A, Ballanti S, Pulini S, Catarini M, Alesiani F, Corvatta L, Gentili S, Caraffa P, Boccadoro M, Leoni P, Palumbo A (2012) Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma. Leuk Lymphoma 53(9):1722–1727PubMedCrossRefGoogle Scholar
  74. Ohtani K, Dimmeler S (2011) Epigenetic regulation of cardiovascular differentiation. Cardiovasc Res 90:404–412PubMedCrossRefGoogle Scholar
  75. Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S (2007) Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109–3115PubMedCrossRefGoogle Scholar
  76. Otterson GA, Hodgson L, Pang H, Vokes EE (2010) Phase II study of the histone deacetylase inhibitor Romidepsin in relapsed small cell lung cancer (Cancer and Leukemia Group B 30304). J Thorac Oncol 5:1644–1648PubMedCentralPubMedCrossRefGoogle Scholar
  77. Pandolfi PP (2001) Histone deacetylases and transcriptional therapy with their inhibitors. Cancer Chemother Pharmacol 48(Suppl 1):S17–S19PubMedCrossRefGoogle Scholar
  78. Parsons PG, Hansen C, Fairlie DP, West ML, Danoy PA, Sturm RA, Dunn IS, Pedley J, Ablett EM (1997) Tumor selectivity and transcriptional activation by azelaic bishydroxamic acid in human melanocytic cells. Biochem Pharmacol 53:1719–1724PubMedCrossRefGoogle Scholar
  79. Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti RS, Dalla-Favera R (2003) Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101:2914–2923PubMedCrossRefGoogle Scholar
  80. Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH (2009) Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 27:5410–5417PubMedCentralPubMedCrossRefGoogle Scholar
  81. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, Jaffe ES, Ling A, Turner M, Peer CJ, Figg WD, Steinberg SM, Smith S, Joske D, Lewis I, Hutchins L, Craig M, Fojo AT, Wright JJ, Bates SE (2011) Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 117:5827–5834PubMedCentralPubMedCrossRefGoogle Scholar
  82. Pili R, Salumbides B, Zhao M, Altiok S, Qian D, Zwiebel J, Carducci MA, Rudek MA (2012) Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. Br J Cancer 106:77–84PubMedCentralPubMedCrossRefGoogle Scholar
  83. Plumb JA, Finn PW, Williams RJ, Bandara MJ, Romero MR, Watkins CJ, La Thangue NB, Brown R (2003) Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2:721–728PubMedGoogle Scholar
  84. Ramalingam SS, Kummar S, Sarantopoulos J, Shibata S, LoRusso P, Yerk M, Holleran J, Lin Y, Beumer JH, Harvey RD, Ivy SP, Belani CP, Egorin MJ (2010) Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. J Clin Oncol 28:4507–4512PubMedCentralPubMedCrossRefGoogle Scholar
  85. Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, Guglielmelli P, Gattoni E, Salmoiraghi S, Finazzi MC, Di Tollo S, D’Urzo C, Vannucchi AM, Barosi G, Barbui T (2010) A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 150:446–455PubMedGoogle Scholar
  86. Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM, Hu J, Dzik-Jurasz A, Yang W, Scher HI (2010) A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 66:181–189PubMedCrossRefGoogle Scholar
  87. Razak AR, Hotte SJ, Siu LL, Chen EX, Hirte HW, Powers J, Walsh W, Stayner LA, Laughlin A, Novotny-Diermayr V, Zhu J, Eisenhauer EA (2011) Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours. Br J Cancer 104:756–762PubMedCentralPubMedCrossRefGoogle Scholar
  88. Ree AH, Dueland S, Folkvord S, Hole KH, Seierstad T, Johansen M, Abrahamsen TW, Flatmark K (2010) Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. Lancet Oncol 11:459–464PubMedCrossRefGoogle Scholar
  89. Riggs MG, Whittaker RG, Neumann JR, Ingram VM (1977) n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268:462–464PubMedCrossRefGoogle Scholar
  90. Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsuruo T, Nakanishi O (1999) A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA 96:4592–4597PubMedCentralPubMedCrossRefGoogle Scholar
  91. Sauve AA, Wolberger C, Schramm VL, Boeke JD (2006) The biochemistry of sirtuins. Annu Rev Biochem 75:435–465PubMedCrossRefGoogle Scholar
  92. Scherpereel A, Berghmans T, Lafitte JJ, Colinet B, Richez M, Bonduelle Y, Meert AP, Dhalluin X, Leclercq N, Paesmans M, Willems L, Sculier JP (2011) Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study. Eur Respir J 37:129–135PubMedCrossRefGoogle Scholar
  93. Stathis A, Hotte SJ, Chen EX, Hirte HW, Oza AM, Moretto P, Webster S, Laughlin A, Stayner LA, McGill S, Wang L, Zhang WJ, Espinoza-Delgado I, Holleran JL, Egorin MJ, Siu LL (2011) Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Clin Cancer Res 17:1582–1590PubMedCrossRefGoogle Scholar
  94. Strickler JH, Starodub AN, Jia J, Meadows KL, Nixon AB, Dellinger A, Morse MA, Uronis HE, Marcom PK, Zafar SY, Haley ST, Hurwitz HI (2012) Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors. Cancer Chemother Pharmacol 70(2):251–258PubMedCentralPubMedCrossRefGoogle Scholar
  95. Ueda H, Manda T, Matsumoto S, Mukumoto S, Nishigaki F, Kawamura I, Shimomura K (1994) FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice. J Antibiot (Tokyo) 47:315–323CrossRefGoogle Scholar
  96. Verdin E, Dequiedt F, Kasler HG (2003) Class II histone deacetylases: versatile regulators. Trends Genet 19:286–293PubMedCrossRefGoogle Scholar
  97. Verdin E, Dequiedt F, Fischle W, Frye R, Marshall B, North B (2004) Measurement of mammalian histone deacetylase activity. Methods Enzymol 377:180–196PubMedCrossRefGoogle Scholar
  98. Wagner JM, Hackanson B, Lubbert M, Jung M (2010) Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics 1:117–136PubMedCentralPubMedCrossRefGoogle Scholar
  99. Walter RB, Medeiros BC, Powell BL, Schiffer CA, Appelbaum FR, Estey EH (2012) Phase II trial of vorinostat and gemtuzumab ozogamicin as induction and post-remission therapy in older adults with previously untreated acute myeloid leukemia. Haematologica 97:739–742PubMedCentralPubMedCrossRefGoogle Scholar
  100. Wang Z, Zang C, Cui K, Schones DE, Barski A, Peng W, Zhao K (2009) Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138:1019–1031PubMedCentralPubMedCrossRefGoogle Scholar
  101. Wang H, Cao Q, Dudek AZ (2012) Phase II study of panobinostat and bortezomib in patients with pancreatic cancer progressing on gemcitabine-based therapy. Anticancer Res 32:1027–1031PubMedGoogle Scholar
  102. Weichert W (2009) HDAC expression and clinical prognosis in human malignancies. Cancer Lett 280:168–176PubMedCrossRefGoogle Scholar
  103. Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, Scarisbrick J, Reddy S, Robak T, Becker JC, Samtsov A, McCulloch W, Kim YH (2010) Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 28:4485–4491PubMedCrossRefGoogle Scholar
  104. Wightman F, Ellenberg P, Churchill M, Lewin SR (2012) HDAC inhibitors in HIV. Immunol Cell Biol 90:47–54PubMedCrossRefGoogle Scholar
  105. Wong NS, Seah E, Wang LZ, Yeo WL, Yap HL, Chuah B, Lim YW, Ang PC, Tai BC, Lim R, Goh BC, Lee SC (2011) Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer. Pharmacogenet Genomics 21:760–768PubMedCrossRefGoogle Scholar
  106. Yong WP, Goh BC, Soo RA, Toh HC, Ethirajulu K, Wood J, Novotny-Diermayr V, Lee SC, Yeo WL, Chan D, Lim D, Seah E, Lim R, Zhu J (2011) Phase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases, SB939, in patients with refractory solid malignancies. Ann Oncol 22:2516–2522PubMedCrossRefGoogle Scholar
  107. Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5:37–50PubMedCrossRefGoogle Scholar
  108. Yoshida M, Kijima M, Akita M, Beppu T (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265:17174–17179PubMedGoogle Scholar
  109. Younes A, Oki Y, Bociek RG, Kuruvilla J, Fanale M, Neelapu S, Copeland A, Buglio D, Galal A, Besterman J, Li Z, Drouin M, Patterson T, Ward MR, Paulus JK, Ji Y, Medeiros LJ, Martell RE (2011) Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol 12:1222–1228PubMedCrossRefGoogle Scholar
  110. Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM, Harrison SJ, Kirschbaum M, Johnston P, Gallagher J, Le Corre C, Shen A, Engert A (2012) Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol 30:2197–2203PubMedCrossRefGoogle Scholar
  111. Zhang Y, Gilquin B, Khochbin S, Matthias P (2006) Two catalytic domains are required for protein deacetylation. J Biol Chem 281:2401–2404PubMedCrossRefGoogle Scholar
  112. Zou H, Wu Y, Navre M, Sang BC (2006) Characterization of the two catalytic domains in histone deacetylase 6. Biochem Biophys Res Commun 341:45–50PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Institute of Pharmaceutical SciencesAlbert-Ludwigs-Universität FreiburgFreiburgGermany

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