Abstract 4719: The HDAC inhibitor ITF2357 blocks c-Myc expression via microRNA modulation and cap-dependent translation inhibition in human Burkitt's lymphoma

Abstract

Abstract Deregulated c-Myc expression plays a critical role in the pathogenesis and progression of aggressive B-cell non-Hodgkin lymphomas (B-NHLs) and multiple myeloma. Chromosomal translocations juxtaposing c-Myc to immunoglobulin gene regulatory elements are virtually invariant, early transforming events in Burkitt's lymphoma (BL), thus constituting the prime example of c-Myc-driven oncogenesis. The key role of c-Myc-mediated epigenetic changes for its oncogenic gene expression reprogramming makes histone deacetylases (HDAC) inhibitors novel suitable drug candidates for the treatment of c-Myc-driven lymphomas. Furthermore, an increasing body of evidence is unraveling the ability of these inhibitors to down-regulate c-Myc expression itself in tumor cells. Therefore, we studied the potential antitumor activity of ITF2357, a new-generation pan-HDACs inhibitor, in human BL pre-clinical models. ITF2357 boosted histone and non-histone protein acetylation in Namalwa and Raji cells, and induced G1 cell-cycle arrest followed by apoptosis especially in the Namalwa model. Treated cells displayed a significant decrease of c-Myc protein but not mRNA levels. This effect was only partially explained by the significant up-regulation of let-7a and miR-26a - two microRNA that negatively control c-Myc expression - since it was not as persistent as c-Myc down-regulation. Given tumor cell addiction to cap-dependent translation for the constitutive expression of short-lived oncoproteins, including c-Myc, we investigated whether this mechanism was also affected by ITF2357. Akt and PIM kinases are the best-defined activators of cap-dependent protein translation initiation via 4E-BP1 phosphorylation and derepression of the translation factor eIF4E. We found that 4E-BP1 and eIF4E phosphorylation as well as phosphorylated-Akt and PIM kinases were significantly down-regulated in the treated cells. Since mTOR and PIM kinase inhibitors display only limited clinical efficacy against B-NHLs, ITF2357 treatment may thus exert a therapeutic advantage, given its ability to concurrently block the redundant oncogenic survival signals that control cap-dependent translation initiation, and potentially overcome the selection of chemoresistance mechanisms. In Raji-xenografted immunodeficient mice, ITF2357-mediated biomolecular effects were translated into 45% tumor shrinkage and complete disease eradication in 70% of the animals when the drug was used as maintenance management after its combination with low-dose cyclophosphamide. Taken as a whole, these findings provide the proof-of-concept for the clinical evaluation of ITF2357 in rational combinations with conventional and unconventional anticancer agents for the treatment of c-Myc-overexpressing and/or cap-translation-dependent NHLs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4719. doi:1538-7445.AM2012-4719