Histone deacetylase inhibitors demonstrate significant preclinical activity as single agents, and in combination with bortezomib in Waldenström's macroglobulinemia

We studied the role of histone deacetylase inhibitors in Waldenstrom's macroglobulinemia (WM). Gene expression profiling of bone marrow CD19+ cells from 30 patients and 10 healthy donors showed overexpression of HDAC4, HDAC9, and Sirt5, with validation of HDAC9 overexpression by q-PCR in primary and BCWM.1 cells. Suberoylanilide hydroxamic acid, trichostatin A, panobinostat, and sirtinol demonstrated dose-dependent killing of BCWM.1 cells. TSA showed the greatest potency with IC50 of 70 nM. Importantly, HDAC9 activity was decreased following TSA treatment suggesting an essential role for this HDAC in WM therapy. The combination of bortezomib plus HDAC inhibitors resulted in at least additive tumor cell killing in BCWM.1 cells. TSA and bortezomib-induced apoptosis depended on a similar set of caspase activation, whereas their effect on cell cycle regulators was distinctly different. These results provided a framework for examining HDAC inhibitors as monotherapy, as well as combination therapy with bortezomib in WM.     

Potential role of miRNAs and their inhibitors in glioma treatment

Recent years have seen an intense period of research on the functions of miRNAs, recently discovered key regulators of gene expression that act through suppression of translation of target mRNAs. Several hundred miRNAs have been identified in humans, and these show characteristic expression patterns, depending on tissue type, cell type or environmental stimuli. Like other types of cancer, the brain tumor glioblastoma shows a distinct miRNA expression signature, and a number of recent studies have linked these miRNA alterations to key hallmarks of glioblastoma including proliferation, survival, invasion, angiogenesis and stem cell-like behavior. These studies have opened the door to the possibility of utilizing miRNAs or miRNA antagonists as therapeutic agents for the treatment of brain tumors.