**6. Epigenetics-Based Therapies for CM**

Given the critical roles of epigenetic alterations in CM development and its drug resistance, targeting or co-targeting these epigenetic events appears to be a promising strategy for improving the clinical condition of CM patients [109]. Although epigenetic biomarkers have not yet found their place in clinical practice, an impressive number of epigenetic drugs are constantly being developed and tested for their cytotoxicity and efficacy in clinical trials in various human cancers, including CM [89,202]. These epigenetic drugs include both general epigenetic inhibitors such as HDACi or DNMTi, but also more specific inhibitors targeting enhancer of zeste homolog 2 (EZH2i), bromodomain and extra-terminal domain proteins (BETi), or JMJD3 and JARID1B demethylases [203]. Table 1 summarizes the current status of those CM therapies (Table 1).

**Table 1.** Overview of the most common epigenetic inhibitors and their current status in CM <sup>1</sup> .



**Table 1.** *Cont*.

1 (-) none; (+) combination therapy.

DNA methylation and histone acetylation were the first and most extensively studied epigenetic alterations in cancer. The progress made in understanding them led to the development of DNA methyltransferase inhibitors (DNMTIs) and histone deacetylase inhibitors (HDACi), which constitute the first generation of epigenetic inhibitors [39]. These firstgeneration epigenetic inhibitors were tested in clinical trials either alone or combined with other therapeutic agents; notably, these molecules showed limited selectivity and stability, increased cytotoxicity, and low efficiency in solid tumors especially when employed as a single therapy [235]. Their clinical use is currently restricted to hematological malignancies: myelodysplastic syndromes and leukemias. The low efficacy of epi-therapies in solid tumors compared to blood cancers is still poorly understood. One possible explanation may be that these agents reach their therapeutic concentrations more efficiently in blood cancers so that their short life may not affect their activities as it may do in solid tumors [236]. Another explanation refers to the fact that solid and hematological tumors differ considerably in terms of cell differentiation and epigenetic plasticity, with solid tumors originating from a more terminally differentiated state that is much more difficult to be transcriptomically reprogrammed [39].

The introduction of the second-generation of epi-drugs, which included certain DN-MTi (such as zebularine and guadecitabine) and HDACi (belinostat, panobinostat, hydroxamic acid, tucidinostat, and valproic acid) has brought considerable advantages over its predecessors. These compounds have improved pharmacological properties, fewer side effects, and amplified selectivity, their targets being key drivers or pivotal regulators of tumor growth [202]. Despite the scientific efforts devoted to its development, the second generation of epigenetic drugs also showed reduced efficacy when administered as monotherapy [237]. This called for the development of the third generation of epi-therapies, which include, among others, histone methyltransferase inhibitors (HMTi), histone demethylase inhibitors (HDMi), enhancer of zest homolog 2 inhibitors (EZH2i), and bromodomain and extra-terminal domain inhibitors (BETi) [39]. The development of the third generation of epi-drugs took into account the principles of precision medicine, in which the existence of a high degree of selectivity is a supreme desideratum [39]. The development of the third generation of epi-drugs revealed that epigenetic factors that can write, erase or read epigenetic marks are usually protein complexes, emphasizing that a better understanding of the epigenetic regulators' interactome may help to design more effective and selective epi-therapies [238]. In this section we will review the current status of epigenetic therapies used either as single agents or in combination with conventional approaches in CM.
