H-26071 ADVL0916 - A PHASE I STUDY OF VORINOSTAT AND BORTEZOMIB IN CHILDREN WITH

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Vorinostat (Suberylanilide hydroxamic acid (SAHA), Zolinza¿, IND #71976) is a histone deacetylase inhibitor that inhibits the activity of histone deacetylases (HDACs). HDACs repress gene transcription. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors. Inhibition of HDAC activity results in an open chromatin structure and transcriptional activation. In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.1 Bortezomib (PS-341, Velcade¿, IND #58443) is a reversible small molecule inhibitor of the 26S proteasome that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. Bortezomib exerts its antitumor effect through several distinct mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration, and angiogenesis. The disruption of normal homeostatic mechanisms can lead to cell death.2 The combination of vorinostat and bortezomib has been shown to be synergistic in vitro in a variety of malignancies, including hepatoma,3 multiple myeloma, leukemia, lymphoma and gastrointestinal cancer. These studies showed that there are multiple levels of potential interaction between vorinostat and bortezomib which could explain their observed synergistic activity. These include NF-B inhibition, increased reactive oxygen species production, increased levels of cyclin-dependent kinase inhibitors, increased proteasome inhibition, and increased expression of tumor suppressor genes such as p53, E2F, and Bax. Additionally, vorinostat may disrupt bortezomib-induced aggresome formation resulting in increased cell stress and apoptosis.11 Phase 1 trials in adults of vorinostat in combination of bortezomib demonstrate that this drug combination was generally well-tolerated. This is a phase 1 study of vorinostat administered orally on days 1-5 and 8-12 in combination with bortezomib administered intravenously on days 1, 4, 8, and 11 of a 21 day cycle. It is designed to determine safety of this drug combination in children with refractory or recurrent solid tumors. The correlative studies will assess NF-B inhibition and endoplasmic reticulum stress response in peripheral blood mononuclear cells (PBMC) before and after treatment.