The failure of epigenetic combination therapy for cancer and what it might be telling us about DNA methylation inhibitors.

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Epigenetic changes in cancer are well described, and it is believed aberrant DNA hypermethylation and histone deacetylation can lead to silencing of tumor suppressor genes and tumorigenesis [1]. Epigenetic therapy is progressively growing in importance as a class of therapies for cancer. Currently seven drugs are approved by the US FDA for the treatment of a variety of cancers, and target two major epigenetic systems. Those drugs that inhibit DNA methylation and those drugs that inhibit histone deacetylation (Table 1). Epigenetic therapies have demonstrated clear benefit in patients with some cancers via randomized clinical trials [2,3]. However, conclusive evidence that these drugs function via an epigenetic mechanism does not exist. In fact, studies combining epigenetic therapies have been disappointing and may suggest these agents do not act via an epigenetic target [4–6]. Azacitidine (Vidaza) and decitabine (Dacogen) are DNA methyltransferase inhibitors (DNMTi). Both are cytosine analogs that incorporate into the DNA and irreversibly inhibit DNA methyltransferase leading to a decrease in DNA methylation. Both DNMTi are approved as single-agent treatment of myelodysplastic syndrome (MDS), a hematologic malignancy closely related to acute myelogenous leukemia (AML) [7,8]. Both drugs are used at clinically low doses which are believed to take advantage of the DNA methylation inhibition properties as opposed to the cytotoxic properties of these drugs. Clinically decreases in gene-specific DNA methylation and global DNA methylation have been shown with these drugs [9,10]; however, reactivation of a specific tumor suppressor gene has not been shown to be associated with response in MDS. In addition, global DNA methylation decreases appear to be transient and rapidly return to baseline levels after the treatment is stopped or in between treatment cycles [9]. Azacitidine was compared in a randomized clinical trial to another cytosine analog, cytarabine. In this study cytarabine was given at both low doses and higher doses. Azacitidine was clearly shown to improve survival compared with both low-dose and high-dose chemotherapy [2]. Interestingly the rate of complete response (eradication of the disease and normalization of the bone marrow) was higher with intensive chemotherapy, but the clinical outcome was better with low-dose chronic azacitidine treatment [2]. Perhaps contrasting a killing the cancer strategy for intensive chemotherapy versus a modification of the phenotype by epigenetic therapy. The failure of epigenetic combination therapy for cancer and what it might be telling us about DNA methylation inhibitors