Targeting Epigenetics for Cancer Therapy: Scores of Agents Capture Interest of Researchers

Jane de Lartigue, PhD
Published: Friday, Nov 01, 2013
If we think of the genome as the cellular genetic manual, then the “epigenome” essentially tells the cell how to read the manual—a secondary level of genetic modification that does not affect the structure of genes, but determines when and where they will be expressed. As with the mutations that can occur in our genetic structure, epigenetic abnormalities can also drive the development of cancer. However, unlike genetic mutations, epigenetic changes are reversible, and as such, drugs that restore the epigenetic balance represent exciting potential therapeutic targets for cancer.

Figure. Epigenetic Processes

Epigenetic Processes

Ac indicates acetylation; CpG, cytosine base precedes guanine; Me, methylation.

What Is Epigenetics?

A universal definition of epigenetics remains somewhat elusive, but essentially it describes a second layer (literally, epi means “upon or over”) of regulation that acts upon the genome and directs the spatial and temporal expression of genes.

DNA Methylation Methyl groups can be added to both adenine and guanine bases in DNA and, among many important functions, methylation helps to guide proper cellular development, altering the expression of key genes as cells divide and differentiate. Methylation most commonly occurs on the cytosine of CpG dinucleotides (points in the DNA structure where a cytosine base precedes a guanine, hence CpG), where it functions to suppress gene expression. CpGs are often clustered in “islands” around the part of the DNA that initiates expression (the promoter), and these CpG islands are mostly unmethylated in normal cells (Figure).

Histone Modification Because histones are proteins, they can be modified after translation by acetylation, methylation, phosphorylation, ubiquitination, and other groups. The nucleosome is composed of eight core histone molecules with two loops of DNA wrapped around them (Figure). The “tails” of the histones protrude from the nucleosome, and it is here that they are usually modified. The addition of these chemical groups serves to attract activating or repressing complexes to the chromatin, which affects its shape and makes particular areas more or less available for gene expression. The specific pattern of histone modifications found in a genome is often called the “histone code.”

Epigenetic modifications are laid down and removed by chromatin-modifying enzymes. DNA methylation is catalyzed by DNA methyltransferases (DNMTs). There are three active DNMTs in eukaryotes: DNMT3A and DNMT3B, which are responsible for de novo methylation, and DNMT1, which maintains existing methylation patterns.

Histone modifications are catalyzed by enzymes specific to the particular kind of modification. The most common histone modifications are acetylation, orchestrated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and methylation, catalyzed by histone methyltransferases (HMTs) and histone demethylases (HDMs).

Take-Home Messages

  • Epigenetic alterations, such as DNA methylation and histone modifications, regulate the temporal and spatial expression of genes contained in the human genome.
  • Epigenetic abnormalities are frequent events implicated in the development of many different types of cancer.
  • Five drugs that target and inhibit enzymes responsible for epigenetic changes are approved by the FDA.
  • Scores of epigenetic agents are in various stages of clinical testing.
  • Epigenetic modifications have the potential to provide biomarkers for response and disease detection.
  • Epigenetic agents have significant synergistic potential in combination with traditional agents, and many combination trials are currently under way.
In addition to chromatin-modifying enzymes that catalyze the addition (“writers”) and removal (“erasers”) of epigenetic marks, there is a third class (“readers”) that bind to specific epigenetically modified regions of the genome and recruit certain proteins. Among the readers of histone acetylation are proteins that contain bromodomains (eg, the BET family BRD2, 3, 4, and BRDt).

Other Epigenetic Modifications

Nearly the entire genome is transcribed, converted from RNA to DNA. However, only 2% is subsequently translated into protein. The remainder is known as noncoding messenger RNA (mRNA), and may also play a significant role in epigenetic regulation at the level of protein translation. For example, one type of noncoding mRNA, known as microRNA (miRNA), functions to regulate gene expression and interact with coding mRNA to inhibit its translation into protein.

Epigenetic Deregulation in Cancer

Cancer is traditionally thought of as a disease caused by the accumulation of genetic mutations. However, epigenetic abnormalities have also been implicated in the development of many different types of cancer, and in fact, are vastly more frequent events than mutations.

The first epigenetic modification that was linked to cancer was methylation. Cancer cells typically display a state of global hypomethylation (reduced methylation), but the CpG islands that surround the promoter are commonly hypermethylated (increased methylation). Approximately 5% to 10% of CpG islands that are normally nonmethylated become abnormally methylated in cancer cells.

Histone methylation and acetylation are also frequently dysregulated in cancer cells. Alterations can be common to multiple different cancer types, or they can be very tumor-specific (eg, low H3K4 methylation levels in breast cancer patients, high H3K9 acetylation levels in lung cancer patients). miRNAs are also dysregulated in cancer, though it is much more difficult to determine which miRNAs have clinical significance in cancer development.

Table 1. FDA-Approved Epigenetic Therapies

Agent Class Company Approval Date Approved Indication Basis of Approval
Azacitidine (Vidaza) DNMT inhibitor Celgene Corporation 2004 FAB myelodysplastic syndrome subtypes Phase III trial demonstrating a 15.7% ORR (primary analysis) and 165.5-day median duration of partial response or better
Decitabine (Dacogen) DNMT inhibitor Eisai 2006 Myelodysplastic syndrome Phase III trial demonstrating a 17% ORR (in ITT population) and a 288-day median duration of response
Vorinostat (Zolinza) Pan-HDAC inhibitor Merck 2006 Cutaneous T-cell lymphoma Phase IIB trial demonstrating a 29.7% ORR and a median duration of response not reached but estimated at >6 months
Romidepsin (Istodax) Class I HDAC inhibitor Celgene Corporation 2009 Cutaneous T-cell lymphoma 2 studies demonstrating 34%-35% ORRs and 11-15-month median duration of response
Ruxolitinib (Jakafi) JAK1/2 inhibitor Incyte Pharmaceuticals 2011 Intermediate or highrisk myelofibrosis Phase III COMFORT-I (vs placebo) and COMFORT-II (vs best available therapy) trials demonstrating 41.9% of patients at 24 weeks and 28.5% of patients at 48 weeks, respectively, with spleen volume reduction ≥35% from baseline

DNMT indicates DNA methyltransferase; HDAC, histone deacetylase; ITT, intent to treat; JAK, Janus kinase; ORR, overall response rate. Source: Prescribing information for individual agents.

Genetic mutations and epigenetic changes are intricately linked since driver mutations affecting epigenetic players, particularly the chromatin-modifying enzymes, are common causes of epigenetic dysregulation (eg, DNMT3A mutations are found in up to 25% of patients with acute myelogenous leukemia).

Epigenetic dysregulation ultimately leads to changes in the pattern of gene expression so that tumor-promoting genes are activated, while tumor-suppressor genes are silenced. It also leads to a misinterpretation of the histone code, generating changes in the overall chromatin structure, and drives genomic instability, making genes more susceptible to mutation, which further reinforces the development of cancer. It has been found to occur very early in the progression of cancer and, as such, may have an important role in establishing the supportive microenvironment needed for cancer development. Epigenetics also plays a role in development of chemoresistance to existing drugs.

Epigenetic-Targeting Therapies

Given the significant role that has been uncovered for epigenetic modifications in cancer development, there has been a substantial amount of interest in exploiting this role to restore a “normal” epigenetic landscape via epigenetic-targeted therapeutics.

Thus far, clinical success with epigenetic therapy has been limited to agents targeting the chromatin-modifying enzymes. Several agents are approved by the FDA for treatment of hematologic malignancies, including two DNMT inhibitors and two HDAC inhibitors (Table 1). A number of phase II and III trials are also under way with these agents in a variety of cancer types.

There are two general types of HDAC inhibitors: pan inhibitors that are broad-acting, and inhibitors that target a specific class of HDAC enzyme. For example, vorinostat is a pan inhibitor, while romidepsin is a class I-specific drug. More HDAC inhibitors are in clinical trials than any other class of epigenetic agent (Table 2).

Several novel HDAC inhibitors are also in advanced stages of clinical development, including the broad inhibitors panobinostat and belinostat and the class I inhibitor entinostat. The FDA recently awarded entinostat Breakthrough Therapy status, a designation that allows expedited development and review for a novel therapy that demonstrates substantial clinical improvement over existing therapies in one or more clinically significant endpoints. Data from the phase II ENCORE 301 study of entinostat in patients with metastatic, estrogen receptor-positive breast cancer indicated that it extended both progression- free and overall survival when added to exemestane. Entinostat is now entering phase III trials in breast cancer and is undergoing phase I/II testing in a range of other cancer types.

Three naturally occurring small molecules have been found to have HAT inhibitory activity: curcumin, anacardic acid, and garcinol. Curcumin, the active ingredient in turmeric, is in phase II trials in advanced pancreatic, breast, and colorectal cancer (NCT00094445, NCT01740323, NCT01490996). HMT and HDM inhibitors, such as BIX-01294, chaetocin, and DZNep, are primarily in a preclinical stage of development. However, the HDM inhibitor phenelzine sulfate, a monoamine oxidase A inhibitor, is in phase II trials in combination with docetaxel in prostate cancer (NCT01253642).

Table 2. Selected Epigenetic Therapies in Clinical Development

Agent Class Sponsors Stage of Development
Panobinostat (LBH589) Pan-HDAC inhibitor Novartis Phase III trials in Hodgkin lymphoma and multiple myeloma; phase II/III study in cutaneous T-cell lymphoma
(NCT01034163, NCT01023308, NCT00425555)
Entinostat (MS-275, SNDX-275) Class I HDAC inhibitor Syndax Pharmaceuticals, National Cancer Institute Phase I and II trials in a range of indications including Hodgkin lymphoma and kidney cancer Phase II trial in breast cancer led to FDA designation as a Breakthrough Therapy in 2013. Phase III trial in breast cancer is recruiting.
(NCT00866333, NCT01038778, NCT01349959)
Belinostat (PXD101) Pan-HDAC inhibitor TopoTarget/ Spectrum Pharmaceuticals, National Cancer Institute Phase II trials in T-cell lymphoma, non-small cell lung cancer, ovarian cancer, hematologic tumors
(NCT00357032, NCT01310244, NCT00274651, NCT00301756)
Pracinostat (SB939) HDAC inhibitor MEI Pharma/ Synteract HCR, NCIC Clinical Trials Group Phase II trials in myelodysplastic syndrome, acute myeloid leukemia, metastatic/recurrent sarcoma (NCT01873703, NCT01912274, NCT01112384)
Givinostat HDAC inhibitor Italfarmaco Phase II trial in myeloproliferative neoplasms (NCT01761968)
Phenelzine sulfate HDM inhibitor OHSU Knight Cancer Institute/ National Cancer Institute Phase II trial in prostate cancer
Epigallocatechin gallate (green tea extract) DNMT inhibitor Barbara Ann Karmanos Cancer Institute/National Cancer Institute Phase II trial in multiple myeloma (NCT01589887)
Valproic acid HDAC inhibitor MD Anderson Cancer Center Phase II trial in breast cancer

DNMT indicates DNA methyltransferase; HDAC, histone deacetylase; HDM, histone demethylase. Source: NIH Clinical Trials Registry,

Histones are also phosphorylated by a number of kinase enzymes, which already have well-established roles in cancer development through the signaling pathways that they regulate. The contribution of their histone phosphorylation function to cancer development is less clear, except in the case of Janus kinase 2 (JAK2), which phosphorylates H3Y41 and has been shown to have a clear role in chromatin signaling. The JAK1/2 inhibitor ruxolitinib is FDA-approved for treatment of intermediate- or high-risk myelofibrosis, and is also being investigated in lymphoma and pancreatic cancer.
The two FDA-approved DNMT inhibitors, 5-azacitidine and decitabine, are very nonspecific, and there is significant room to improve their efficacy. Newer DNMT inhibitors, including S110 (a modified form of decitabine that is more stable and may allow for more prolonged drug exposure) and CP-4200, are in preclinical trials and demonstrate potent cytotoxic activity.

A novel pharmacologic strategy has come to light in recent years, as researchers have developed the ability to target protein–protein interactions with small-molecule inhibitors. Drugs are being designed that target the interaction between histones and the “reader” proteins, particularly the bromodomain- containing BET. For example, PFI-1 is in preclinical trials and has been observed to downregulate the transcription of a number of oncogenes.

downregulate the transcription of a number of oncogenes. Epigenetic changes may also serve as useful biomarkers, both for detecting disease and predicting therapeutic efficacy in patients with cancer. For example, the hypermethylation of the glutathione S-transferase pi 1 (GSTP1) gene is observed in 85% of prostate cancers but not in benign prostatic hyperplasia, and thus could serve as a potential biomarker for prostate cancer.

Challenges for Epigenetic Therapy

There remain some significant challenges to the development of epigenetic therapy. Most significantly, epigenetic therapies have yet to show substantial efficacy in solid tumors. It is believed that this may be due partly to poor cellular uptake of the drugs. Researchers are designing new drugs that address this issue and have already been able to improve the anticancer efficacy of azacitidine.

Another challenge is to determine the synergistic potential of combination therapy with epigenetic drugs. A multitude of clinical trials already under way are assessing the efficacy of rational combinations of two different types of epigenetic therapy or of these therapies in combination with traditional therapies.

It will also be vital to improve our understanding of the precise mechanism of action of epigenetic therapies, so that potential adverse events can be better predicted. For example, these types of drugs will likely have a long-term impact on the structure of chromatin, and it is important to understand how this will affect cells.

Finally, we will need to better define a “normal” epigenetic landscape. To this end, large-scale analyses are under way using high-throughput technologies, by such organizations as The Cancer Genome Atlas, the International Cancer Genome Consortium, and the National Institute of Health’s Roadmap Epigenome Program, with the ultimate goal of generating a complete map of the epigenome.

Key Research
  • Dawson MA, Kouzarides T. Cancer epigenetics: from mechanisms to therapy. Cell. 2012;150: 12-27.
  • Dawson MA, Kouzarides T, Huntly BJP. Targeting epigenetic readers in cancer. N Engl J Med. 2012;367(7):647-657.
  • Hatzimichael E, Crook T. Cancer epigenetics: new therapies and new challenges. J Drug Delivery. 2013. Article ID 529312.
  • Ho AS, Turcan S, Chan TA. Epigenetic therapy: use of agents targeting deacetylation and methylation in cancer management. OncoTargets and Therapy. 2013;6:223-232.
  • Liu SV, Fabbri M, Gitlitz BJ, Laird-Offringa IA. Epigenetic therapy in lung cancer. Frontiers Oncol. 2013;3(135):1-8.
  • Rodriguez-Paredes, M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17(3):330-339.
  • Waldmann T, Schneider R. Targeting histone modifications—epigenetics in cancer. Curr Opin Cell Biol. 2013;25:184-189.

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