New Approaches to Targeting Epigenetic Regulation in Bladder Cancer

SIMPLE SUMMARY: Epigenetic changes occur in parts of the genome other than in nucleotides. They are considered reversible and are therefore important targets for cancer therapy. Epigenetic changes have been observed in urological cancers, including urothelial carcinoma, and in recent years have been a topic of investigation for the treatment of metastatic bladder cancer that has failed traditional therapy. We performed a review of the current literature to assess the evidence and role for targeted epigenetic therapy in bladder cancer. While we found 25 clinical trials investigating this topic, there have been no phase 3 human clinical trials to date. This is an emerging topic in urology, and future directions involve further research into bladder cancer-specific epigenetic changes, as well as the development of novel agents to target these mutations. ABSTRACT: Epigenetics is a growing field and in bladder cancer, it is of particular interest in advanced or metastatic disease. As opposed to genetic mutations in which the nucleotide sequence itself is altered, epigenetic alterations refer to changes to the genome that do not involve nucleotides. This is of great interest in cancer research because epigenetic alterations are reversible, making them a promising target for pharmacological agents. While chemoimmunotherapy is the mainstay for metastatic disease, there are few alternatives for patients who have progressed on first- or second-line treatment. By targeting reversible epigenetic alterations, novel epigenetic therapies are important potential treatment options for these patients. A search of clinical registries was performed in order to identify and collate epigenetic therapies currently in human trials. A literature search was also performed to identify therapies that are currently in preclinical stages, whether this be in vivo or in vitro models. Twenty-five clinical trials were identified that investigated the use of epigenetic inhibitors in patients with bladder cancer, often in combination with another agent, such as platinum-based chemotherapy or pembrolizumab. The main classes of epigenetic inhibitors studied include DNA-methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and histone methyltransferase (HMT) inhibitors. At present, no phase 3 clinical trials have been registered. Few trials have published results, though DNMT inhibitors have shown the most promise thus far. Many patients with advanced or metastatic bladder cancer have limited treatment options, particularly when first- or second-line chemoimmunotherapy fails. Epigenetic alterations, which are common in bladder cancer, are potential targets for drug therapies, and these epigenetic agents are already in use for many cancers. While they have shown promise in pre-clinical trials for bladder cancer, more research is needed to assess their benefit in clinical settings.