Epigenetic targets in hematological malignancies: combination therapies with HDACis and demethylating agents.
Chromatin modeling in DNA is fundamental to gene expression, DNA repair and replication. Methylation of promoter regions of tumor-suppressor genes and histone deacetylation leads to gene silencing and transcriptionally repressive chromatin. Histone deacetylase inhibitors and hypomethylating agents allow upregulation of proapoptotic genes and downregulation of antiapoptotic genes, and show significant single-agent anticancer activity, predominantly in cutaneous T-cell lymphoma and myelodysplasia, respectively. Combinations of these drugs are being employed in clinical trials to target multiple biological pathways, with the hope of synergistic pharmacodynamics. Preclinical studies of combinations of these agents with chemotherapy, monoclonal antibodies and small-molecule inhibitors are ongoing and demonstrate synergy in multiple hematological cancers, raising the prospect of future treatment for these diseases having a multitargeted approach.
Bishton
Mark
M
Peter MacCallum Cancer Center, Department of Haematology, Melbourne, Australia. mark.bishton@petermac.org
Kenealy
Melita
M
Johnstone
Ricky
R
Rasheed
Walid
W
Prince
H Miles
HM
D000107:Acetylation / Q000187:drug effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D019175:DNA Methylation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D004357:Drug Synergism; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004273:DNA, Neoplasm; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D006655:Histone Deacetylases