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• W2400187771 abstract "Epigenetic reprogramming erases the malignant potential of some transformed cells. The aim of epigenetic therapy is to achieve some degree of reprogramming in-vivo through reversing epigenetic changes and reactivating important genes including tumor-suppressor genes. It is hoped that this strategy will modify the malignant phenotype and induce clearance of the malignant clone by various mechanisms, including apoptosis, senescence and an immune response. Epigenetic modifying agents may also have mechanisms of anticancer action unrelated to gene reactivation. The DNA methyltransferase inhibitors azacitidine, decitabine and guadecitabine induce clinically meaningful remissions or improvements in 30-60% of patients with myeloid leukemias and prolong survival compared to standard approaches including chemotherapy. This therapy is accompanied by (i) global and gene specific demethylation, (ii) reactivation of silenced gene expression, (iii) delayed responses that correlate with early epigenetic reactivation and result in clonal elimination and (iv) eventual relapses and resistance the mechanisms of which appear to involve genetic evolution in some cases. Two strategies have been proposed to enhance the efficacy of DNMT inhibitors - targeting other epigenetic pathways and unbiased screens for epigenetic activity. Using gene expression as an endpoint, we compared inhibitors of DNMTs (decitabine, DAC), HDACs, G9A, EZH2 and LSD1 in-vitro. We find that DNMT inhibition is the most specific approach to reactivation of genes silenced in cancer and, while HDAC inhibition is also very effective, it also has the highest rate of non-specific effects, which may explain why adding HDAC inhibitors to DNMT inhibitors has been disappointing clinically to date. Drugs that inhibit G9A, EZH2 or LSD1 had modest effects on their own but showed significant, non-overlapping synergy with DAC, while preserving specificity. To perform unbiased screens for epigenetic activity, we used a live cell assay based on DNA methylation mediated silencing of a CMV transgene driving GFP expression. In a screen of FDA approved drugs, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that reactivate GFP as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides and arsenic trioxide, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity leading to MeCP2 phosphorylation and its nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. In a separate screen for synergy with DNMT inhibition, we found that platinum compounds showed striking synergy in activating GFP. This was dose dependent, observed both in concurrent and sequential combinations, seen with other alkylating agents, and linked mechanistically to significantly inhibited HP1α expression. Our data uncover multiple distinct mechanisms that can be targeted for epigenetic therapy in cancer. Citation Format: Jean-Pierre J. Issa. Multiple targetable pathways for epigenetic therapy. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA23." @default.
• W2400187771 created "2016-06-24" @default.
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• W2400187771 date "2016-01-14" @default.
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• W2400187771 title "Abstract IA23: Multiple targetable pathways for epigenetic therapy" @default.
• W2400187771 doi "https://doi.org/10.1158/1538-7445.chromepi15-ia23" @default.
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