HDAC inhibitor-based therapies and haematological malignancy.

Reversible acetylation mediated by histone deacetylase (HDAC) influences a broad repertoire of physiological processes, many of which are aberrantly controlled in tumour cells. Since HDAC inhibition prompts tumour cells to enter apoptosis, small-molecule HDAC inhibitors have been developed as a new class of mechanism-based anticancer agent, many of which have entered clinical trials. While the clinical picture is evolving and the precise utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumour types undergo a favourable response, in particular haematological malignancies. Vorinostat (suberoylanilide hydroxamic acid) has been approved for treating cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease. Here, we discuss developments in our understanding of molecular events that underlie the anticancer effects of HDAC inhibitors and relate this information to the emerging clinical picture for the application of HDAC inhibitors in haematological malignancies.

[1]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[2]  F. Sherman,et al.  The diversity of acetylated proteins , 2002, Genome Biology.

[3]  P. Matthias,et al.  HDAC‐6 interacts with and deacetylates tubulin and microtubules in vivo , 2003, The EMBO journal.

[4]  J. Leonard,et al.  Multicenter Phase II Trial of the Histone Deacetylase Inhibitor Depsipeptide (FK228) for the Treatment of Relapsed or Refractory Multiple Myeloma (MM). , 2005 .

[5]  N. L. La Thangue,et al.  Histone deacetylase inhibitors: gathering pace. , 2006, Current opinion in pharmacology.

[6]  S. Jagannath,et al.  Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination with Bortezomib in Patients with Advanced Multiple Myeloma. , 2007 .

[7]  T. Fojo,et al.  Update of the NCI multiinstitutional phase II trial of romidepsin, FK228, for patients with cutaneous or peripheral T-cell lymphoma , 2007 .

[8]  M. Grever,et al.  A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. , 2004, Blood.

[9]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[10]  E. D. Jacobsen,et al.  Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  V. Kiermer,et al.  HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis. , 2003, Immunity.

[12]  Ricky W Johnstone,et al.  Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? , 2003, Cancer cell.

[13]  P. Marks,et al.  Histone Deacetylase Inhibitors: Overview and Perspectives , 2007, Molecular Cancer Research.

[14]  Ronald Breslow,et al.  Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug , 2007, Nature Biotechnology.

[15]  Sang Gyun Kim,et al.  Class I Histone Deacetylase-Selective Novel Synthetic Inhibitors Potently Inhibit Human Tumor Proliferation , 2004, Clinical Cancer Research.

[16]  J. Miguel,et al.  Triple Combinations of the HDAC Inhibitor Panobinostat (LBH589) + Dexamethasone with Either Lenalidomide or Bortezomib Are Highly Effective in a Multiple Myeloma Mouse Model. , 2007 .

[17]  C. Schoch,et al.  Clinical trial of valproic acid and all‐trans retinoic acid in patients with poor‐risk acute myeloid leukemia , 2005, Cancer.

[18]  P. Marks,et al.  Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors , 1999, Nature.

[19]  Marie Joseph,et al.  Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[20]  P. Mclaughlin,et al.  A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma , 2007 .

[21]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[22]  A. Bordoni,et al.  Epidemiology of hematological malignancies. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  S. Harrison,et al.  The potential of histone deacetylase inhibitors for the treatment of multiple myeloma , 2008, Leukemia & lymphoma.

[24]  S. Singhal,et al.  A Phase II Study of PXD101 in Advanced Multiple Myeloma. , 2006 .

[25]  Chun Li Zhang,et al.  Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy , 2002, Cell.

[26]  T. Kuzel,et al.  Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  G. Rosner,et al.  Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. , 2008, Blood.

[28]  Minoru Yoshida,et al.  [Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A]. , 1990, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[29]  Linda Z Sun,et al.  Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma , 2008, Leukemia & lymphoma.

[30]  A. Bosi,et al.  A Phase II Multiple Dose Clinical Trial of Histone Deacetylase Inhibitor ITF2357 in Patients with Relapsed or Progressive Multiple Myeloma: Preliminary Results. , 2007 .

[31]  P. D. Paepe,et al.  Diffuse large B-cell lymphoma: a heterogeneous group of non-Hodgkin lymphomas comprising several distinct clinicopathological entities , 2007, Leukemia.

[32]  M. Minden,et al.  Myelodysplastic syndromes: the complexity of stem-cell diseases , 2007, Nature Reviews Cancer.

[33]  John M. Shelton,et al.  Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis , 2004, Cell.

[34]  P. Richardson,et al.  Novel therapies in myeloma , 2007, Current opinion in hematology.

[35]  Chunlei Zhang,et al.  Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). , 2007, Blood.

[36]  Jeffrey W. Scott,et al.  Phase IA/II Study of Oral LBH589, a Novel Deacetylase Inhibitor (DACi), Administered on 2 Schedules, in Patients with Advanced Hematologic Malignancies. , 2007 .

[37]  V. Rybin,et al.  HDAC6–p97/VCP controlled polyubiquitin chain turnover , 2006, The EMBO journal.

[38]  T. Fojo,et al.  Phase II Trial of Romidepsin, FK228, in Cutaneous and Peripheral T-Cell Lymphoma: Clinical Activity and Molecular Markers. , 2006 .

[39]  C. Steidl,et al.  The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia , 2006, Cancer.

[40]  J. Becker,et al.  Clinically Significant Responses Achieved with Romidepsin in Treatment-Refractory Cutaneous T-Cell Lymphoma: Final Results from a Phase 2B, International, Multicenter, Registration Study , 2008 .

[41]  R. Advani,et al.  Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma: Results of a Phase II Study. , 2007 .

[42]  M. Duvic,et al.  Clinical and laboratory experience of vorinostat (suberoylanilide hydroxamic acid) in the treatment of cutaneous T-cell lymphoma , 2006, British Journal of Cancer.

[43]  M. Salto‐Tellez,et al.  Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1 , 2005, Cell Death and Differentiation.

[44]  John McAnally,et al.  MEF2C transcription factor controls chondrocyte hypertrophy and bone development. , 2007, Developmental cell.

[45]  R. Bernards,et al.  Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. , 2009, Cancer cell.

[46]  B. Turner,et al.  An increasingly complex code. , 2002, The Journal of clinical investigation.

[47]  Nicola Pimpinelli,et al.  WHO-EORTC classification for cutaneous lymphomas. , 2005, Blood.

[48]  U. Germing,et al.  Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. , 2004, Blood.

[49]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[50]  A. Zelenetz,et al.  Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  P. Mclaughlin,et al.  Treatment of Relapsed or Refractory Lymphoma with the Oral Isotype-Selective Histone Deacetylase Inhibitor MGCD0103: Interim Results from a Phase II Study. , 2007 .

[52]  T. Kuzel,et al.  Primary cutaneous lymphomas: a review with current treatment options. , 2003, Blood reviews.

[53]  N. L. La Thangue,et al.  Chromatin control and cancer-drug discovery: realizing the promise. , 2006, Drug discovery today.

[54]  P. Murray,et al.  Contribution of the Epstein–Barr virus to the molecular pathogenesis of Hodgkin lymphoma , 2006, Journal of Clinical Pathology.

[55]  N. L. La Thangue,et al.  Biomarkers for predicting clinical responses to HDAC inhibitors. , 2009, Cancer letters.

[56]  L. Schwartz,et al.  Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  L. Cuppini,et al.  The histone deacetylase inhibitor ITF2357 has anti-leukemic activity in vitro and in vivo and inhibits IL-6 and VEGF production by stromal cells , 2007, Leukemia.

[58]  J. Vance,et al.  The Deacetylase HDAC6 Regulates Aggresome Formation and Cell Viability in Response to Misfolded Protein Stress , 2003, Cell.

[59]  M. Grever,et al.  Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[60]  L. F. Glass,et al.  The diagnosis, staging, and treatment options for mycosis fungoides. , 2007, Cancer control : journal of the Moffitt Cancer Center.

[61]  E. Olsen,et al.  Vorinostat provides prolonged safety and clinical benefit to patients with advanced cutaneous t-cell lymphoma (CTCL) , 2008 .

[62]  M. Krstic-Demonacos,et al.  Acetylation control of the retinoblastoma tumour-suppressor protein , 2001, Nature Cell Biology.

[63]  W. Wilson,et al.  Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. , 2001, Blood.

[64]  K. Savage.  Peripheral T-cell lymphomas. , 2007, Blood reviews.

[65]  K. Glaser,et al.  Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. , 2003, Molecular cancer therapeutics.

[66]  R. Bociek,et al.  Isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 demonstrates clinical activity and safety in patients with relapsed/refractory classical Hodgkin Lymphoma (HL) , 2008 .

[67]  M. Keegan,et al.  Safety and Efficacy of the Combination of Bortezomib with the Deacetylase Inhibitor Romidepsin in Patients with Relapsed or Refractory Multiple Myeloma: Preliminary Results of a Phase I Trial. , 2007 .

[68]  E. Sausville,et al.  Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. , 2007, Blood.

[69]  K. Glaser.  HDAC inhibitors: clinical update and mechanism-based potential. , 2007, Biochemical pharmacology.

[70]  M. Minden,et al.  Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. , 2008, Blood.