Abstract P088: Combined inhibition of histone deacetylases and EZH2 for the treatment of Wilms tumors

Abstract

Abstract Wilms tumor (WT) is the most common childhood kidney cancer. It is believed to arise from immature kidney cells–nephron progenitor cells (NPCs)—which have failed to differentiate properly. Altered epigenetics is central to oncogenesis in many pediatric cancers. The critical contribution of epigenetic dysregulation to pediatric tumors provides a compelling rationale for the therapeutic potential of epigenetic drugs. Histone deacetylases (HDACs, especially HDAC1/2) and Enhancer of Zeste Homolog 2 (EZH2), a histone H3K27 methyltransferase, have been demonstrated to play a critical role in self-renewal and differentiation of mouse nephron progenitor cells (NPCs). In addition, altered expression and mutations of HDACs and EZH2 have been linked to many human cancers, including WT. As such, they are among the most promising therapeutic targets for cancer treatment. For sinstance, the treatment of Panobinostat, an FDA-approved pan-HDAC inhibitor, leaded to apoptosis and growth suppression of WT cells. EZH2 is highly expressed in WT and has been demonstrated to be associated with WT progression. We reasoned that WT results from unrestrained proliferation of progenitor cells due to overactive HDAC1, HDAC2, and EZH2. To prove this, we collected 5 human WT specimens. Immunostaining demonstrated dramatically higher level of HDAC1, HDAC2, SIX1, and SIX2 in the tumor tissues compared with adjacent normal tissues, strongly suggesting a critical role for the overactive HDAC1/2 in the SIX1/2 activation to promote cell proliferation in WT. Gain-of-function of SIX1 or SIX2 has been demonstrated to be closely correlated with high proliferation and aberrant differentiation of WT. Importantly, SIX2 marks the cancer stem cell population in WT. In addition, knockdown of HDAC1/2 by siRNAs or CRISPR gene editing resulted in downregulation of SIX1/2 in human embryonic kidney 293 cells and G401 cells derived from a Wilms tumor. Published studies also showed that treatment of Trichostain (a potent pan HDAC inhibitor) significantly reduced the Six1 expression in vertebrate neural crest and Hodgkin lymphoma cells. All these support the regulation of SIX1/2 expression by HDAC1/2. Concomitant inhibition of HDACs and EZH2 has proven to be highly synergistic and very potent for the treatment of many types of human cancers. Promisingly, combined treatment benzamide-based HDAC1/2-selective inhibitor Merck60 and Tazemetostat (an FDA-approved EZH2 inhibitor) synergistically suppressed cell growth in a wide range of dose combinations in 293T and G401 cells. In summary, our studies demonstrated elevated expression and activity of HDAC1/2 in WT, positive regulation of SIX1/SIX2 by HDAc1//2 during tumorigenesis, and synergic effect of HDAC1/2 and EZH2 inhibition in suppressing tumor cell proliferation. Thus, targeting HDAC1/2 and EZH2 may provide a promising therapeutic approach to treat WT and other pediatric kidney cancer with low toxicity and low side effects. Furthermore, availability of epigenetic drugs will facilitate the translation of this research into effective therapies. Citation Format: Hongbing Liu, Nhi Ngo, Chao-Hui Chen, Samir S. El-Dahr. Combined inhibition of histone deacetylases and EZH2 for the treatment of Wilms tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P088.