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. Data from our group indicate that retinoid resistance in many solid tumors inversely correlates with levels of intracellular retinol and retinol esters, and suggest that increasing intracellular levels of retinoic acid (RA) will improve RA mediated anti-tumor effects. Alternatively, enabling RA to become a more potent initiator of transcription would also lead to RA-induced growth inhibition. Recent studies indicate that transcriptional regulation by RA receptors involves modification of chromatin by histone deacetylases (HDACs), which are recruited to RA-target genes by nuclear co-repressors. Histones are part of the core proteins of nucleosomes. Acetylation and deacetylation of histones play a role in regulation of gene expression (4). Histones in their deacetylated state cause chromatin to be tightly wound around the histone cores, inhibiting transcription. When histones are in their hyperacetylated state (i.e. when deacetylation is inhibited), the chromatin relaxes and transcription can proceed. The levels of histone acetylation are regulated by two classes of enzymes, histone acetyl transferases (HATs) and HDACs. Numerous studies show that HDAC inhibitors can induce cultured tumor cells to undergo differentiation, growth arrest and/or apoptosis. HDACs may prevent RA-induced transcription by not allowing transcription to proceed. Based on these studies and our own preliminary work, we propose to study the combination of ATRA-IV and the HDAC inhibitor Depakote (valproic acid). The long-term goal of this study is to determine the Phase II dose of these agents in combination to proceed to Phase II clinical trials, and to understand the mechanisms of RA and HDAC inhibition in vivo.
The specific aims of this study are: 1) To determine the maximum tolerated dose of Depakote in combination with liposome encapsulated all-trans retinoic acid (ATRA-IV) in patients with advanced solid tumor malignancies; 2) To define the dose limiting and other toxicities of the combination therapy; 3) To determine the dosing that should be used in future safety and efficacy (Phase II) trials; 4) To study retinoic acid receptor expression and histone acetylation status to ascertain biologic effect on peripheral blood mononuclear cells and tissue obtained from selected patients who undergo tumor biopsies; and 5) To assess for tumor responses to combination therapy.
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