COG ADVL0416: A PHASE 1 STUDY OF SAHA IN PEDIATRIC PATIENTS WITH RECURRENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a phase I study of suberoylanilide hydroxamic acid (SAHA) in children and adolescents with recurrent or refractory solid tumors or leukemia. SAHA is an inhibitor of histone deacetylase (HDAC) that causes the arrest of cell cycle transition at G1 and G2M phases. It has been reported to selectively induce expression of p21 waf/CIP1 cyclin-dependent kinase inhibitor, to effect cell cycle arrest1 and to induce p53 independent apoptosis. A possible model for the antitumor action of SAHA is the inhibition of HDAC activity causing the activation of transcription of genes whose expression force tumor differentiation, apoptosis or inhibit tumor growth. Retinoid acid receptors recruit co-regulatory complexes with HDAC activity in the absence of a ligand, which results in repression of gene transcription. This study will be done in 3 parts.