Epigenetic therapy in urologic cancers: an update on clinical trials

Abstract

Epigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.

The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma

“…12,13 Clinical studies evaluating the efficacy of epigenetic regulators in multiple tumor types are currently underway, including the use of histone deacetylase inhibitors (HDACi) and DNA methyltransferases inhibitors (DNMTi). [14][15][16][17][18][19][20] HDACi act primarily by increasing acetylation of histones, leading to a more open chromatin configuration and allowing gene transcription, thus reversing repression of genes in cancer cells. 21 In addition, HDACi also lead to increased acetylation of other targets of HDACs beyond histones, including transcription factors, which likely also play a role in their effects on cancer cells.…”

Engineering Multidimensional Evolutionary Forces to Combat Cancer

“…Histone modifications have become a frequent area of focus and include histone acetylation, deacetylation, and methylation. Several histone deacetylase (HDAC) inhibitors are currently in clinical use in multiple different cancer subtypes with additional clinical trials ongoing (111,112). In NSCLC, EMT is affected by histone acetylation (101).…”

“…MiRNAs are another type of epigenetic mechanism that is more recently recognized. They are small endogenous noncoding RNA segments that can regulate gene expression, and inhibit or promote cancer by targeting messenger RNAs for activation or deactivation (111,112). Multiple preclinical studies have demonstrated their potential both to monitor therapeutic response and as a therapy target (124).…”

Introductory Chapter: Current Studies in Transcriptional Control System; Toward the Establishment of Therapies against Human Diseases

“…Currently, candidate drugs that target HDAC [55][56][57] and DNMTs [56,57] are under clinical tests and expected to contribute to the development of novel cancer therapeutics. Epigenetic alterations on genomic DNAs is not only associated with cancer generation, but also with neurologic diseases [58], autoinflammatory diseases [59], and metabolic diseases, including type II diabetes [60].…”