Epigenetics in Cancer: What's the Future?
Epigenetics in Cancer: What's the Future?
ABSTRACT: Epigenetics is a rapidly expanding field that focuses on stable changes in gene expression that are not accompanied by changes in DNA sequence and that are mediated primarily by DNA methylation and histone modifications. Disruption of the epigenome is a fundamental mechanism in cancer, and several epigenetic drugs that have proved to prolong survival and to be less toxic than conventional chemotherapy were recently approved by the FDA for cancer treatment. These include azacitidine (Vidaza), decitabine (Dacogen), vorinostat (Zolinza), and romidepsin (Istodax). Promising results of combination clinical trials with DNA methylation inhibitors and histone deacetylase inhibitors have recently been reported, and data are emerging that describe molecular determinants of clinical responses. Despite significant advances, challenges remain, including a lack of predictive markers, unclear mechanisms of response and resistance, and rare responses in solid tumors. Preclinical studies are ongoing with novel classes of agents that target various components of the epigenetic machinery. In this review, we focus on recent clinical and translational data in the epigenetics field that have potential in cancer therapy.
Epigenetics is defined as the study of stable changes in gene expression that are not accompanied by changes in DNA sequence. Epigenetic changes are important biological processes with relevance to all multicellular organisms. Studies in various models have shown that epigenetic regulation is critical for proper embryogenesis and development. Several mechanisms of epigenetic change have been described, and all seem to be interdependent to some degree. DNA methylation, posttranslational modifications of histones, and chromatin remodeling enzymes mediate epigenetic changes in many organisms. It has become clear that disruption of the epigenetic machinery plays a fundamental role in cancer development. Tumors often exhibit global hypomethylation, hypermethylation of CpG islands, and genome-wide alterations in the levels of histone modifications. These abnormalities are associated with widespread changes in gene expression, which are thought to contribute to tumor formation by affecting oncogenes and tumor suppressor genes.
What Is Epigenetic Therapy?
The understanding that epigenetic changes are prevalent in cancer and play a causative role in its biology has led to the development of new therapeutic approaches that target the epigenetic machinery. The first successful drugs developed as epigenetic agents were DNA methyltransferase inhibitors; these were followed by histone deacetylase inhibitors (HDIs). Both classes of drugs aim at reversing gene silencing and demonstrate antitumor activity in vitro and in vivo. Several other classes of drugs have been developed that target various other components of the epigenetic machinery; one such class is the histone methyltransferases, with new drugs in this class currently in early preclinical development (Table 1).
What Has Been Done?
The inhibitors of DNA methylation used clinically are nucleoside analogues that get converted into deoxy-nucleotide-triphosphates (dNTPs) and become incorporated into DNA in place of cytosine during DNA replication. They trap all DNA methyltransferases and target them for degradation. At low doses these drugs do not inhibit proliferation; they reactivate gene expression and have shown clinical activity as anticancer agents. Azacitidine (AZA; Vidaza) was the first hypomethylating agent approved by the FDA; its approval, in 2004, for the treatment of myelodysplastic disorders and leukemia, was followed by the approval, in 2006, of decitabine (DAC; 5-aza-2′-deoxyctidine; Dacogen).[2,3] Both drugs produce remissions or clinical improvements in more than 30% of patients treated. Features of responses have included the requirement for multiple cycles of therapy, slow response, and relatively few side effects. On the molecular level, demethylation, gene reactivation, and clonal elimination were observed in treated patients. The data in myelodysplastic syndrome (MDS) represent a proof-of-principle for epigenetic therapy for cancer, in particular in myeloid disorders.
HDIs work by preventing histone deacetylation, thereby facilitating an open chromatin structure and leading to the activation of genes, including the p21 cyclin-dependent kinase inhibitor. Several HDIs have shown antitumor activity in vitro with little toxicity in preclinical studies, suggesting selectivity for neoplastic cells. This has prompted the development of additional compounds, many of which have entered phase 1 trials in various malignancies. Two HDIs have shown particular efficacy against cutaneous T cell lymphoma (CTCL)—response rates of over 30%—which led to the FDA approval of vorinostat (suberoylanilide hydroxamic acid; Zolinza) in 2007 and of romidepsin (depsipeptide; Istodax) in 2009.[5,6]
Recent Clinical Trials
So far, all four FDA-approved epigenetic drugs have shown the greatest efficacy in hematopoietic malignancies. There is no known reason why this should be true, or why solid tumors would not respond as well. Older studies suggested a lack of activity for these agents in various solid tumors; however, most testing was done at high doses, with short exposures, and in patients with refractory disease—conditions also associated with lack of response in hematologic malignancies. There may be pharmacologic or pharmacodynamic reasons that favor responses in leukemias (eg, drug uptake, proportion of proliferating cells), but the activity of these agents in solid tumors certainly deserves a second look. Here, we describe recent clinical advances with FDA-approved and investigational epigenetic agents, both in hematologic malignancies and in solid tumors (Table 2).
AZA was recently tested in a phase III trial in MDS. The overall response rate in the first report was 21%, with documented improved survival compared with either supportive care or chemotherapy.[7,8] In a subset analysis, improved survival was also seen in patients with acute myeloid leukemia (AML). The combination of AZA with lenalidomide (Revlimid) in high-risk MDS showed a promising 67% overall response rate in a phase I study. A phase II study demonstrated a decrease in platelet transfusion dependence for patients receiving AZA plus romiplostim (Nplate).
Several phase II trials have demonstrated substantial activity for DAC as a single agent in AML, resulting in a complete response (CR) in 24% to 52% of patients; the drug appears to be especially promising for older patients.[12,13] A recent early combination trial of DAC with carboplatinum showed some activity in platinum-resistant ovarian cancer and demonstrated demethylating activity, thus justifying further clinical efficacy testing.
Results of a phase I study of vorinostat in patients with leukemias have been reported. Seven patients (17%) achieved a CR, a CR with incomplete blood count recovery, or hematological improvement; all had AML. Promising results were recently shown in advanced non–small-cell lung cancer (NSCLC), where vorinostat vs placebo was used in addition to the combination of carboplatinum and paclitaxel. Vorinostat significantly enhanced the efficacy of chemotherapy in patients with advanced NSCLC (overall response rate, 34% vs 12.5%), and there was a trend toward improvement in median progression-free survival and overall survival in the vorinostat arm. Modest responses were recently demonstrated in non-Hodgkin lymphoma and glioblastoma multiforme with vorinostat used as a single agent; it would be interesting to test it in combination regimens in the future.[17,18] A phase I study in patients with colorectal and gastric carcinomas tested the first clinical combination of an HDI with therapeutic radiation, and it found the combination to be well tolerated and safe. Change in tumor volume was evaluable in 14 patients and showed considerable variation, ranging from a 54% reduction to a 28% increase (mean, 26% reduction). These data will underpin future chemoradiation studies of vorinostat combined with radiotherapy.
Final results of a phase II multicenter study in CTCL have been published; a 34% response rate was achieved in a refractory setting, making the use of romidepsin an important therapeutic option for this disease. Romidepsin showed minimal activity in MDS and low-level activity in AML in a phase I trial; interestingly, responses were seen only in a subgroup of core binding factor leukemias.
Panobinostat is one of the most potent HDIs in vitro, and preliminary studies have shown activity in CTCL. More recently, promising phase I results were demonstrated in refractory Hodgkin lymphoma  and in prostate cancer; a decline in PSA levels was reported in 60% of patients in an early trial of panobinostat in combination with docetaxel (Taxotere).
An early phase I study of belinostat, another potent HDI, in combination with carboplatinum and/or paclitaxel was recently conducted; this trial showed some activity of belinostat in various solid tumors, although it is unclear whether the addition of belinostat was superior to chemotherapy alone. Another phase II study showed some activity in ovarian cancer.
Valproic acid is a short-chain fatty acid that is a weak HDI. A single-agent study demonstrated minor responses in patients with MDS. Most of the clinical data on valproic acid have come from combination studies. A larger trial of valproic acid and epirubicin/5-FU/cyclophosphamide showed 22% partial responses in solid tumors. Another phase I/II trial of valproic acid with a topoisomerase I inhibitor in metastatic melanoma showed 47% disease stabilization.