Abstract 2631: The HDAC inhibitor PCI-24781 potentiates the anti-tumor activity of tamoxifen in ER-positive breast cancer cells

Abstract

Abstract The anti-estrogen tamoxifen remains the treatment of choice for patients with estrogen receptor (ER)-positive breast cancer. Although initially very effective, patients responsive to tamoxifen will eventually develop resistance and progress. Thus, the development of new therapies to combat breast cancer is needed. An emerging strategy to modulate ER signaling has been to employ histone deacetylase (HDAC) inhibitors. Preclinical studies from our and other laboratories have shown that HDAC inhibitors potentiate the anti-tumor activity of tamoxifen by promoting apoptosis. We have further shown that select depletion of HDAC2 is sufficient to elicit synergistic cell death when combined with tamoxifen, indicating it as a relevant target for this combined therapy. In a recent phase II clinical trial conducted by our laboratory, durable responses were observed in patients with metastatic ER-positive breast cancer when the HDAC inhibitor vorinostat was co-administered with tamoxifen. To evaluate HDAC inhibitor activity, histone acetylation in surrogate peripheral blood mononuclear cells was measured in patients pre- and post-treatment. This analysis indicated that increased histone acetylation correlated with patient response. Increased acetylation was observed in only 58% of patients, suggesting that greater HDAC inhibition would lead to the enrichment of patients likely to benefit. Furthermore, patient response correlated with baseline expression of HDAC2. Therefore, a more potent inhibitor of HDAC2 may provide greater benefit in patients when combined with tamoxifen. PCI-24781 is a hydroxamic acid inhibitor that targets class I and II HDACs. Preclinical data demonstrates anti-tumor activity against a variety of hematological and solid tumor malignancies when administered at nanomolar concentrations. Early phase clinical evaluation has shown that PCI-24781 is tolerable at these concentrations. As PCI-24781 is 8 times more potent against HDAC2 compared to vorinostat (IC50: 19 nM vs 164 nM, respectively), we sought to evaluate the effectiveness of combining PCI-24781 with tamoxifen against breast cancer. At clinically feasible doses, we found that PCI-24781 potentiates the anti-tumor activity of tamoxifen in various ER-positive breast cancer cell lines (e.g. MCF-7, BT474, and MDA-361). This combination induces cell death by activating the apoptotic program, as measured by PARP cleavage and TUNEL staining. Furthermore, growth is inhibited by attenuating ER signaling, illustrated by down-regulation of ER protein and its pro-growth response genes (e.g. PR, Cyclin D, and Myc). Therefore, early preclinical evaluation demonstrates that PCI-24781 enhances the effectiveness of tamoxifen in vitro and may represent a more potent combination for combating breast cancer. Mouse xenograft studies are on going to determine whether this benefit translates in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2631. doi:10.1158/1538-7445.AM2011-2631