Development of Oral Suberoylanilide Hydroxamic Acid

Sloan-Kettering Institute For Cancer Res, New York NY

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Abstract

Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylase (HDAC) that induces growth arrest, differentiation and/or apoptosis of several human tumor cell lines and xenograft. Accumulations of acetylated histones can be detected in vitro and is a useful biological marker of SAHA activity at the cellular level. Inhibition of HDAC can alter expression of a number of gene products (i.e.p21WAF1) but the clinical significance of these gene alterations is not known. Initial studies in humans using daily intravenous infusions of SAHA for up to 3 consecutive weeks have shown hat SAHA is safe; there is an accumulation of acetylated histones in peripheral mononuclear ells and in tumors post-therapy; and that SAHA does have anti-tumor activity in patients. These results are encouraging, but further development of SAHA is contingent on the availability of an oral formulation that would permit chronic dosing. Our group developed an oral formulation and we have approval to conduct a phase I study (IND 58,915; MSKCC IRB approval data 02-15-01; activation date: 7-030-01) with the oral SAHA. This study will determine the maximal tolerated dose for phase II studies, the pharmacokinetic profile and oral bioavailability of oral SAHA and document any anti-tumor effects from the therapy. To further understand the biological effect of SAHA in patients, we will assess the changes in acetylated histones in peripheral mononuclear cells and tumor biopsies and genes regulated by the SAHA (i.e.p21WAF1) in tumors. Subsequently, these findings will be correlated with the clinical outcomes.