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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 961-970

Epigenetic therapies in patients with solid tumors: Focus on monotherapy with deoxyribonucleic acid methyltransferase inhibitors and histone deacetylase inhibitors


1 Department of Family Practice, Medical University of Silesia (SUM), Katowice-Zabrze, Zabrze, Poland
2 Department of Pharmacy, Medical University of Silesia (SUM), Katowice, Poland

Date of Web Publication4-Oct-2019

Correspondence Address:
Rygiel Katarzyna
Department of Family Practice, Medical University of Silesia (SUM), Katowice-Zabrze; 3 Maja St.13/15, 41-800 Zabrze
Poland
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_403_17

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 > Abstract 


Epigenomics is the study of the gene expression changes due to epigenetic processes and not due to the deoxyribonucleic acid (DNA) base sequence alterations. The key mechanisms of epigenetic regulation include DNA methylation, histone modifications, and noncoding RNAs. Epigenetic alterations in cancer are predominantly linked with hypermethylation of promoters of the tumor suppressor genes, global DNA hypomethylation, and increased expression of histone deacetylases (HDAC). There is a growing need to investigate epigenetic patterns and to provide safe and effective, innovative therapeutic strategies for oncology patients, who did not improve on traditional anticancer regimens. The epi-drugs (e.g., DNA methyltransferase inhibitors, e.g., azacitidine and decitabine and HDAC inhibitors, e.g., vorinostat and romidepsin) have been approved for the clinical use. In this paper, we provide a brief overview of the mechanisms of action and targets for novel epi-drugs, focusing on their potential clinical applications in patients with solid tumors, resistant to standard oncology treatments.

Keywords: Azacitidine, deoxyribonucleic acid methyltransferase inhibitors, epigenetic clinical studies, histone deacetylase inhibitors, solid tumors, vorinostat


How to cite this article:
Katarzyna R, Lucyna B. Epigenetic therapies in patients with solid tumors: Focus on monotherapy with deoxyribonucleic acid methyltransferase inhibitors and histone deacetylase inhibitors. J Can Res Ther 2019;15:961-70

How to cite this URL:
Katarzyna R, Lucyna B. Epigenetic therapies in patients with solid tumors: Focus on monotherapy with deoxyribonucleic acid methyltransferase inhibitors and histone deacetylase inhibitors. J Can Res Ther [serial online] 2019 [cited 2019 Oct 22];15:961-70. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/961/244213




 > Introduction Top


Epigenetics is the study of heritable alterations in gene expression, without changes in the underlying deoxyribonucleic acid (DNA) sequence.[1] Gene expression patterns are regulated through the activity of different epigenetic enzymes, such as DNA and histone methyltransferases, acetyltransferases, and chromatin remodelers. Aberrations of these epigenetic pathways can result in genome-wide alterations in gene expression.[1],[2] Due to abnormal molecular communication between genomic and epigenomic components, in some susceptible patients, various chronic diseases including malignancies (e.g., hematological cancers or solid tumors) can develop.[2] Since cancer has both genetic and epigenetic roots, the recent advances in epigenetics have contributed to “setting the stage” for the development of novel therapeutic options.[3] The main epigenetic mechanisms that regulate activation or silencing of certain genes include DNA methylation (e.g., hypermethylation of promoters of the tumor suppressor genes or global DNA hypomethylation), histone modifications (e.g., increased expression of histone deacetylases [HDAC]), chromatin remodeling, and noncoding RNAs (ncRNAs).[3],[4] Therefore, exploring the mechanisms that play a crucial role in the initiation and progression of cancer (in preclinical studies and clinical trials) will allow to determine some innovative therapeutic targets and invent novel strategies that can be applied in clinical practice.[5] This is particularly important in the management of patients with cancers that are resistant or poorly responsive to conventional treatments. Since epigenetic treatments (e.g., the first generation of DNA methyltransferase (DNMT) and HDAC inhibitors) have been effective in some hematological malignancies (e.g., myelodysplastic syndrome [MDS] and chronic myelomonocytic leukemia [CMML]), this approach is now being explored in neoplastic solid tumors.[6],[7] The malignant solid tumors are even more challenging than the hematological malignancies, with regard to their genetic and epigenetic complexity. However, it should be highlighted that some molecular aberrations, which are present in solid tumors, can be modified, through novel epigenetic medications (used in monotherapy or in combination with classical anticancer treatments) that target the cancer epigenome.[8],[9] In this paper, we provide a brief overview of some innovative epigenetic agents, approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment, based on the data from clinical trials (available at: www.clinicaltrials.gov site) and the medical literature (published over the past 10 years), focusing on the clinical implications, in patients with solid tumors, not responding to standard anticancer treatment. In addition, in the tables, we present some general information, relevant to the epigenetic: therapeutic targets, mechanisms of action, and clinical implications [Table 1], a concept of enzymatic writers, erasers, and readers, including their specific types and roles in epigenetic regulation [Table 2], and trials on epigenetic therapies (using DNA methyltransferase [DNMT] inhibitors and HDAC inhibitors in monotherapy) in patients with various solid tumors (resistant to standard oncology treatment) [Table 3]. In preparing of this review, a PubMed search of English language medical literature was performed using the keywords: “DNA methyltransferase (DNMT) inhibitors,” “Histone Deacetylase (HDAC) inhibitors,” “solid tumors,” “azacitidine,” “decitabine,” “vorinostat,” “romidepsin,” and “epigenetic clinical studies.” The main search timeframe was set up for the past 10 years. The search was supplemented with additional data from cross-references, relevant to the patients with solid tumors, resistant to classical therapy.
Table 1: Epigenetic therapy: Targets, current or emerging epi-drugs, and possible clinical implications in patients with cancer

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Table 2: Enzymes involved in epigenetic control: Types and functions

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Table 3: Trials on epigenetic therapy with DNA methyltransferase inhibitors and histone deacetylase inhibitors (as monotherapy) in patients with malignant solid tumors

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Epigenetic therapy: Targets and possible clinical implications in patients with cancer

Molecular mechanisms that are “in charge of” activating or silencing certain genes (without altering the underlying DNA sequence) play an essential role in the epigenetic regulation of cell cycle. They include DNA modifications, histone posttranslational modifications, small ncRNAs, and recombination of nongenic DNA.[53] Such reactions are conducted by different enzymes, classified according to their structure and function [Table 1].[3],[41] It should be highlighted that the initiation and progression of different types of malignancies are often associated with epigenetic changes that disrupt equilibrium between oncogenes and tumor suppressor genes.[41] For instance, hypermethylation of some tumor suppressor genes (e.g., the ones involved in DNA repair, such as BRCA1, MGMT, and MLH1) as well as signal transduction (e.g., RASSF1A), cell cycle regulation (e.g., p16INK4a), apoptosis (e.g., DAPK and TMS1), and angiogenesis (e.g., THBS1) reflects common examples of neoplastic aberrations.[5],[41]

Moreover, it is important to point out that epigenetic and genetic “dispositions” (sets of unique clinical characteristics) are applicable to different cancers, such as gastric, colorectal, and ovarian. It is expected that such dispositions are based on the main characteristics of these cancers and can provide a novel direction for the development of individualized treatments.[54] For instance, an analysis of abnormal DNA methylation patterns will allow the identification of various subtypes of sporadic colorectal carcinoma (CRC), and the relevant methylation tests can potentially be useful for the early detection of CRC. In addition, LINE-1 hypomethylation can be a possible prognostic marker in both sporadic and inherited CRCs.[55] Furthermore, it should be noted that the epigenetic control of gene expression can be portrayed as a concept of interrelated actions of the three main groups of enzymes: writers, erasers, and readers, which can also represent novel therapeutic targets in oncology [Table 2].[5],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51]

Trials on epi-drugs: Monotherapy with deoxyribonucleic acid methyltransferase inhibitors and histone deacetylases inhibitors in patients with solid tumors

At present, there are two classes of epi-drugs, available for clinical use, namely, DNMT inhibitors and HDAC inhibitors, which block the reactions of DNMTs and HDACs, contributing to epigenetic transcriptional silencing of the mutated genes.[4],[5],[56] This is particularly useful since many malignant cells have aberrations of histone methyltransferases and demethylases as well as overexpression of HDACs. Furthermore, many studies have reported that the HDAC inhibitors can induce an arrest of cancer cell cycle (at G1 or G2-M stage) as well as modify cellular differentiation or cause apoptosis.[5],[56],[57] HDAC inhibitors might also inhibit angiogenesis and metastatic spread and augment cell sensitivity to chemotherapy.[56],[57]

DNMT-inhibitors, which have been approved as anti-cancer agents by the US FDA, and the EMA include: Azacytidine (5-AZA), and decitabine (5-AZA-2′-deoxycytidin), for the therapy of patients with MDS, and CMML.[4],[5],[6],[7] It should be noted that AZA is incorporated into both DNA and RNA in contrast to decitabine (DAC) that is incorporated into DNA only. These differences between two members of the DNMT inhibitor class might indicate that some synergistic effects are possible if both of these medications are used in combination.[7] The second class, HDAC inhibitors, includes for instance: vorinostat (suberoylanilide hydroxamic acid [SAHA]) and romidepsin (cyclic peptide and depsipeptide) that have been approved by the FDA and EMA for the therapy of progressive or recurrent cutaneous T-cell lymphoma.[4],[5],[14] In addition, the FDA has recently approved two other members of this class: panobinostat (in combination with bortezomib and dexamethasone) for the treatment of multiple myeloma [30] and belinostat for the treatment of peripheral T-cell lymphoma.[33] It should be noted that positive effects of treatment with DNMT and HDAC inhibitors in patients with MDS and leukemia “paved the way” to exploring these epi-drugs in patients with different types of solid tumors, resistant to standard oncology treatment. For instance, the therapy with decitabine in patients with cervical, ovarian, and colorectal cancers and with pleural tumors revealed some beneficial results.[58] Recent clinical trials exploring the use of DNMT inhibitors and HDAC inhibitors in monotherapy in patients with advanced tumors resistant to several lines of anticancer treatment are summarized in [Table 3].[10],[11],[12],[13],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[31],[32],[34],[35],[36],[37],[38],[39],[40]

Adverse effects of deoxyribonucleic acid methyltransferase inhibitors and histone deacetylases inhibitors

In general, toxicity of epi-drugs is mild to moderate. Adverse effects of DNMT inhibitors and HDAC inhibitors, based on relevant clinical studies, are presented in [Table 3]. It should be underscored that the DNMT inhibitors, such as AZA and decitabine (which have been studied for the longest time), not only interfere with DNA methylation but also display antiproliferative activity. For this reason, their toxicity is correlated with the applied doses. For instance, at high doses, AZA can cause neutropenia (like many classical anticancer medications).[10],[12] However, for the epigenetic effects, low doses have usually been recommended so that the adverse effects can be minimized. Toxicity of HDAC inhibitors, such as vorinostat (SAHA), includes anemia, anorexia, fatigue, nausea, hyperglycemia, and thrombocytopenia.[15] Other HDAC inhibitors can cause some gastrointestinal side effects and impair hematopoiesis.[31],[32] In addition, romidepsin can cause cardiac toxicity.[40] Another concern with the use of these two classes of epi-drugs, in patients with cancer, is related to potential genome-wide effects that may cause undesirable upregulation of prometastatic genes. To prevent such detrimental events, the development of gene-targeted epigenetic modifications, in specific tumors, can offer a helpful approach, to maximize the patient safety.[8],[41]

Perspectives on personalized medicine and epigenome profile in solid tumors

Currently, majority of medical practice is based on “standards of care” that is determined by averaging therapeutic results, based on clinical trials, across large patient populations. However, an intriguing phenomenon that patients with the same type of cancer can have different symptoms and either satisfactorily or poorly respond to standard medical treatment has been observed for a long time. In attempt to solve this dilemma, the concept of personalized medicine has emerged, according to which the management of one's health should be based on the individual patient's characteristics (e.g., age, gender, height, weight, family or personal medical history, and lifestyle). According to the US National Cancer Institute definition, a personalized or precision medicine is a form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat diseases. In particular, in cancer, this personalized approach uses specific information about a person's tumor, to help with diagnostic workup and therapeutic plan.[59] It is expected that ongoing efforts to analyze epigenetic changes in DNA, microRNAs, and proteins will help identify biomarkers for patient's classification into subgroups with various susceptibility to certain diseases or with diversified therapeutic responses to specific medications.[8],[59] Furthermore, Gene Expression Human Maps will provide reference maps of epigenomes and some specific genes, involved in oncogenic signaling pathways, oncogenic phenotypes, and procancer reprogramming.[8],[60] It should be emphasized that every type of solid tumor has a specific oncogenic phenotype, characterized by a particular combination of genomic and epigenomic features.[8],[60] For instance, an individual patient with a certain type of cancer may display a specific phenotypical subtype, with both genomic and epigenomic alterations. Such a specific profile needs to be further identified, to determine the exact pathophysiology of a given malignancy, and to design precise therapeutic targets.[8],[59],[60]

For many solid tumors, metastatic spread is the main cause of disease deterioration or patient's death.[8],[60] Metastasis indicates that the malignant cells have acquired epithelial-to-mesenchymal transition (EMT). EMT is a cellular program, regulated by some pleiotropic transcriptional factors, including: Twist, Snail, Slug, and Zeb1/2, which create a circuit that acts as a transcriptional repressor of E-cadherin and zona occludens-1.[61] This, in turn, leads to dissolution of adherens and tight junctions.[61] Induction of EMT is associated with reprogramming of the epigenome, including alterations in DNA methylation, and some posttranslational histone modifications. In the future, different epigenetic regulators, participating in EMT, may be used for individualized, targeted epigenetic therapy of solid tumors.[61]

Biomarkers and clinical response indicators: Challenges and potential solutions

The application of epigenetic inhibitors in the treatment of solid tumors still has many therapeutic challenges, including, for instance, identification of genome and epigenome signaling pathways, in each tumor type and in every individual patient's profile. For this reason, both biomarkers and clinical criteria need to be outlined.[62] Numerous studies have investigated the methylation status of gene promoters and their correlations with clinical parameters in patients with hematological malignancies and solid tumors. Different methodologies have been used (e.g., methylation-specific polymerase chain reaction), and single genes or panels of genes in microarrays were analyzed.[62] In solid tumors, multiple methylated genes have been described, and some associations between changes in the cancer cell epigenome, clinical parameters, and survival or response to treatment have been reported. However, no markers have yet been identified for the clinical use (e.g., to guide diagnostic workup or treatment, including medication dosing, timing, and route of delivery).[62] In individualized anticancer therapy, it is necessary to identify genes, whose transcriptional silencing influences sensitivity to antineoplastic therapies. Furthermore, it is crucial to translate these data into clinically feasible tests, which will guide anticancer treatments. Moreover, panels of genes will be required to help with individual patient management, but such tests are not available yet.[62]

In the meantime, it is essential to collect data on tumor heterogeneity (e.g., through cancer registries, worldwide) and to prioritize possible tumor biomarkers, in context of personalized medicine and prevention.[63] For this reason, a detailed understanding of intratumor and intertumor environment is crucial.[63] Furthermore, it should be highlighted that tumor cells, host cells, and the tumor microenvironment are influenced by genomic variations and by hormonal, dietary, lifestyle, and environmental exposures. Every tumor has its own unique characteristics at molecular and tissue level, and also with regard to interactions with its microenvironment.[63] Since each patient displays a unique epigenetic signature and behavior of solid tumors is difficult to predict, more research is required in order to develop epigenetic biomarkers and diagnostic tools to classify patients into subpopulations that differ in their susceptibility to a specific cancer and in their response to a particular therapy.[63] In addition, patients treated with epi-drugs may show therapeutic results several months after starting the treatment. In such patients, it is critical to identify molecular biomarkers, associated with positive or negative clinical responses, during a posttreatment stage. Quantitative changes in signaling molecules, involved in the oncogenic pathways, can be used as predictive biomarkers.[63] In particular, tumor-associated gene expression and molecular epigenetic biomarkers (e.g., DNA methylation patterns in tumor-associated genes or histone posttranslational changes, such as the CpG island methylator phenotype in specific genes) can be used for prognostic criteria in individual patients, in the future.[64] At present, induced pluripotent stem cell (iPSC) technology has also been applied in various types of cancer, including solid tumors, for disease modeling and gene therapy. Furthermore, application of iPSCs represents a promising option for pharmacology research.[65]

Difficulties with assessment of patients with solid tumors treated with epi-drugs

In several clinical studies, in patients with solid tumors (unresponsive to standard treatment), where the antitumor activities of epi-drugs (DNMT inhibitors and HDAC inhibitors) used in monotherapy were analyzed, the findings were usually presented in terms of reduction of tumor volume (according to the standard for the evaluation of traditional antiproliferative agents). In fact, some of these trials revealed negative reports [Table 3]. To evaluate the tumor burden, in oncology clinical trials, the Response Evaluation Criteria In Solid Tumors (RECIST) has commonly been applied (e.g., for the clinical assessment of the efficacy of new anticancer agents).[66] However, it should be pointed out that the therapeutic responses that have been assessed, based on the RECIST (an appropriate “tool” for conventional anticancer therapies), may not by accurate for evaluation of epigenetic treatment results that are mostly relevant to the neoplastic disease stabilization, rather than the decrease in tumor size only.[67] Therefore, in addition to searching for innovative biomarkers, as an attempt to overcome this challenge, the patient-reported outcome (PRO) measures (e.g., quality of life) have been linked with objective clinical end points and can be helpful, with regard to a prognosis for survival outcomes, in patients with solid tumors.[67] Recently, PROs have been considered as clinically relevant tools, especially since the classical clinical end points do not reflect a full appreciation of the epigenetic treatment effects. In particular, correlations of PROs with treatment responses and patient survival, in patients with cancer, participating in clinical trials, can help medical professionals and their patients with solid tumors, better understand the benefits and risks relevant to epi-drugs, and make the most reasonable decisions, under the specific clinical circumstances.[67],[68]


 > Conclusions Top


The interrelated epigenetic mechanisms of DNA methylation, histone modifications, and ncRNAs influence gene expression and contribute to the cancer initiation and progression in hematologic malignancies and various solid tumors. Epigenetic therapy is emerging as a potential therapy for solid tumors, and the epi-drugs, such as DNMT inhibitors and HDAC inhibitors, induce phenotypical changes in cancer cells, by reactivation of epigenetically silenced tumor suppressor genes. These epi-drugs have impact on several cell signaling pathways. Since cancer cells dysregulate many of the cellular signaling pathways, the precisely targeted epi-drugs (able to reverse some of these aberrant pathways) could potentially overcome certain therapeutic obstacles and lead to more favorable outcomes, among oncology patients with resistant tumors. Lower doses of epi-drugs are beneficial since they allow to achieve the genetic and epigenetic “reprogramming” effects in cancer cells and simultaneously cause less toxicity in surrounding healthy tissues. Moreover, matching epigenetic therapies with the individual patient's clinical characteristics, personal needs, goals, or preferences, aimed at improving survival and quality of life, is in line with the principles of personalized medicine.

In summary, potential clinical utility of DNMT inhibitors and HDAC inhibitors has been confirmed, in patients with solid tumors. However, ongoing collaborative, interdisciplinary efforts of researchers and clinicians, focused on selecting precise epigenetic targets, as well as designing and developing novel epi-drugs are certainly needed. In addition, choosing specific patients populations and accurate outcome measures or biomarkers, while conducting clinical trials on epigenetic therapies (alone and in combination with standard chemotherapy, radiotherapy, hormonal therapy, or immunotherapy) in patients with malignant solid tumors would be merited. Finally, further, longitudinal, larger clinical trials should also explore the connections between genomic/epigenomic findings and clinical characteristics in context of patient's lifestyle/environmental risk factors and individual epigenetic profiling. Unquestionably, further trials need to demonstrate safety, efficacy, and outcome results, before introduction of innovative epi-drugs into the clinical practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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