Epigenetics in Cancer: What's the Future?
Epigenetics in Cancer: What's the Future?
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]