Abstract
Urological cancers are a heterogeneous group of malignancies accounting for a considerable proportion of cancer-related morbidity and mortality worldwide. Aberrant epigenetic traits, especially altered DNA methylation patterns constitute a hallmark of these tumors. Nonetheless, these alterations are reversible, and several efforts have been carried out to design and test several epigenetic compounds that might reprogram tumor cell phenotype back to a normal state. Indeed, several DNMT inhibitors are currently under evaluation for therapeutic efficacy in clinical trials. This review highlights the critical role of DNA methylation in urological cancers and summarizes the available data on pre-clinical assays and clinical trials with DNMT inhibitors in bladder, kidney, prostate, and testicular germ cell cancers.
Highlights
Urological cancers, comprising those primarily originating in bladder, kidney, prostate and testis, are an heterogeneous class of malignancies accounting for significant morbidity and mortality worldwide (Ferlay et al, 2010)
One of the major challenges regarding the use of epigenetic therapies is the establishment of a therapeutic window that may reduce treatment-related toxicity, mostly preserving normal tissues and selectively targeting tumor cells
Despite the successful results achieved in pre-clinical studies and contrarily to hematological malignancies, DNA methylation inhibitors (DNMTi) monotherapy clinical trials in solid tumors have not shown significant anti-cancer efficacy, far (Issa and Kantarjian, 2009)
Summary
Urological cancers, comprising those primarily originating in bladder, kidney, prostate and testis, are an heterogeneous class of malignancies accounting for significant morbidity and mortality worldwide (Ferlay et al, 2010). In an organoid culture model, treatment with 5-aza-2′-deoxycytidine induced DNA demethylation which suppressed the proliferation of intestinal tumor organoids through activation of expression of genes involved in anti-viral response, including interferon-responsive genes (Saito et al, 2016) These findings indicate that DNMTi might modulate both innate and adaptive immune responses against cancer cells. Procaine was able to reduce by 40% the 5-mC DNA content and densely demethylate hypermethylated CpG islands, such as those located in the RARβ2 promoter region, with concomitant re-expression of epigenetically silenced genes This agent exerted growth-inhibitory effects in MCF-7 breast cancer cell line by inducing mitotic arrest (Villar-Garea et al, 2003). Apre-clinical in vivo study with single-agent SGI 110 and 5-aza-2′-deoycytidine in murine xenograft models derived from BlCa cell lines was conducted Both intraperitoneal and subcutaneous administration of the drugs effectively reduced CDKN2A promoter methylation levels, inducing its expression, and inhibited murine tumors growth. It was observed a clinical benefit concerning progression-free survival and overall survival of 5.6 months and 5.7 months, respectively (Candelaria et al, 2007)
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