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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA096228-02
Application #
6626279
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Xie, Heng
Project Start
2002-03-01
Project End
2005-02-28
Budget Start
2003-06-12
Budget End
2005-02-28
Support Year
2
Fiscal Year
2003
Total Cost
$334,640
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Krug, Lee M; Curley, Tracy; Schwartz, Lawrence et al. (2006) Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid. Clin Lung Cancer 7:257-61
Kelly, William Kevin; O'Connor, Owen A; Krug, Lee M et al. (2005) Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 23:3923-31