Histone clinical study

Various epigenetic targets have been investigated in drug discovery approaches. So far only HDAC and DNA methyltransferase (DNMT) inhibitors are approved for the treatment of human cancer or are currently investigated in clinical studies [69]. The search for histone methyltransferase inhibitors is far less developed. 

Fig. 1) daily. This resulted in the reduction and disappearance of the myeloblasts, which was reported in the early 1980s. At the time the mechanism of action was unknown, but increased levels of histone acetylation was observed. Based upon this therapeutic response, butyric acid was then studied in clinical trials. Unfortunately, these trials failed to reproduce the early success of butyric acid. This was likely a result of butyric acid s short-half life ( 6m), poor distribution/bioavailability at the target site, and low Cnax (50... 

Giles, F., Fischer, T., Cortes, J., Garcia-Manero, G., Beck, J., Ravandi, F. et al. (2006) A phase 1 study of intravenous LBF1589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clinical Cancer Research, 12, 4628 635. 

Apart from DNA methylation studies, the second aspect of epigenetic misregulation involves disruption of histone acetylation and chromatin structure. Functional disruption of some HATs genes (such as the CBP and p300) is detected in some cancers, most notably, acute pro-myelocytic leukemia (51). This has lead to the hope that HD AC inhibitors will be useful for the treatment of this disease and a number of inhibitors are currently being assessed in clinical trials (see below). 

Tan J, Gang S, Ma Y, Petrillo RC, Lu D. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. J Hemat One 2010 3(5) 8722-5. Finazzi G, Vannucchi AM, Martinelli V, Ruggeri M, Nobile F, Specchia G, et al. A phase 11 study of Givinostat in combination with hydroxycarbamide in patients with polycythemia vera unresponsive to hydroxycarbamide monotherapy. Brit J Haem 2013 161(5) ... 

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