Potentiation of Topo Inhibitors by the HDACi, SAHA

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DESCRIPTION (provided by applicant): Histone deacetylase inhibitors (HDACi) are a promising new class of anti-cancer agents. Several HDACi are currently in clinical trials as single agents. Treatment of cells with HDACi leads to acetylation of histones, therefore HDACi may play an important role in gene regulation and chromatin structure. Mechanistic studies from cell culture and xenograft models from our lab suggest that HDACi may potentiate DNA damage induced by anti-tumor agents that depend on access to the DNA. Of particular interest are the topoisomerase II inhibitors (topo II). Topo II are essential enzymes that are preferentially expressed in dividing cancer cells and the efficacy of topo II inhibitors has been associated with the expression of topo II isoform, topo lla. Our preclinical data indicate that exposure of tumor cells to HDACi resulted in hyperacetylation of histones. Histone hyperacetylation was associated with a down-regulation of several proteins essential for the maintenance of chromatin structure and subsequent chromatin decondensation. The HDACi-induced chromatin decondensation increased the binding of DNA to topo II inhibitors. In the presence of their targets, this resulted in a potentiation of topo II inhibitor-induced DNA damage and apoptosis. These effects were most profound when cells were treated with HDACi for at least 48 hours. Synergy was abrogated with shorter pre-exposure. Synergistic activity strongly correlated with pre-treatment expression levels of topo II. However, in the setting of HDACi-mediated chromatin decondensation, not only topo lla, but also topo lIb appeared to be an important target. These observations provide a strong rationale to combine HDACi with topo II inhibitors, as the pre- exposure to HDACi may selectively enhance the anti-tumor activity of topo II inhibitors while limiting their toxicity to normal tissues. We will test these observations in a clinical trial and its associated correlative studies by the following aims: Specific Aim 1 describes a sequence-specific Phase I trial where the toxicity, safety and pharmacokinetics of suberoylanilide hydroxamic acid (SAHA) and doxorubicin will be explored. Specific Aim 2 involves correlative studies evaluating the effects of SAHA on histone acetylation, chromatin remodeling and DNA damage induced by doxorubicin in tumor biopsies. Early trials with SAHA suggest that it is well tolerated and may have anti-tumor activity. Doxorubicin was chosen as it is one of the most often used and most effective drugs in cancer therapy. This proposal may help to establish a new paradigm for sequence-specific combinations of HDACi and topo II inhibitors and provide further insight into the mechanism of synergy. These findings may be useful in the rational design of future clinical trials involving HDACi.