It’s 10 p.m. on a Friday night, and you’re still stuck in the lab doing ChIP assays. As the piercing whine of the sonicator frays your last nerve, you ask yourself again, “Why did I go into epigenetics research…why couldn’t I have chosen something simpler and more straightforward (like rocket science)?” At times like these, it’s encouraging to know that the epigenetics research you do today might someday translate into life-saving therapies.
The first generation of FDA-approved epigenetics-based drugs has firmly established that epigenetic modulation is a viable treatment option for a growing list of diseases. The four epigenetic drugs available for clinical use in the U.S. include two DNA demethylating agents, 5-azacytidine and decitabine, and two histone deacetylase (HDAC) inhibitors, vorinostat and valproic acid. The latter two drugs work by blocking HDACs, enzymes that remove acetyl groups from histone tails. 5-azacytidine and decitabine inhibit DNA methyltransferase enzymes, causing reduced overall levels of DNA methylation. Both classes of epigenetic drugs are thought to function, at least in part, by de-repressing genes silenced in disease, such as tumor suppressor genes.
So far, epigenetic drugs have been approved mainly for the treatment of blood cancers, in particular myelodysplastic syndromes (MDS). Often resulting from environmental exposures such as benzene, chemotherapy, or radiation, MDS are characterized by defects in blood precursor cell differentiation in the bone marrow. About 30% of patients with MDS progress to acute myelogenous leukemia (AML).
Before DNA-methylating agents were clinically available, treatment for MDS consisted primarily of repeated blood transfusions. Even with weekly transfusions, patients with the most severe form of the disease could expect to survive for less than two years after diagnosis. According to Kathy Heptinstall, Operating Director of the MDS Foundation, “When I talked to patients, I could say nothing positive to make them believe they could live with the disease.”
In 2004, this situation changed dramatically with the FDA approval of 5-azacytidine, sold under the trade name Vidaza (Celgene, Summit, NJ), for the treatment of MDS. A large phase III clinical study showed that Vidaza almost doubles the 2-year survival rate of MDS patients compared with conventional care (Lancet Oncol. 2009, 10:223), and many patients on Vidaza become transfusion independent.
A recent study by Steven Gore and co-workers might explain Vidaza’s efficacy in MDS (Blood 2009, 114:3448). “We identified about 600 genes that are more methylated in MDS than in normal progenitor cells and about 600 genes that undergo demethylation when people are treated with azacytidine,” says Gore, a Professor of Oncology at Johns Hopkins University.
Interestingly, Vidaza’s deoxy derivative, decitabine (sold under the trade name Dacogen; Eisai, Inc., Woodcliff Lake, NJ), has failed to demonstrate a survival advantage for MDS in two phase III clinical trials. Unlike decitabine, azacytidine is incorporated into RNA as well as DNA, but whether this explains Vidaza’s enhanced efficacy is unknown. “There’s a clear understanding of how Vidaza demethylates DNA,” says Jay Backstrom, Vice President of Clinical Development for MDS at Celgene. “But at the end of the day, how Vidaza exerts its clinical benefit and to what extent incorporation into RNA or downstream effects play a role are still areas of active research.”
What does the future hold for epigenetic therapies? Several clinical trials are investigating combinations of epigenetic drugs with each other or with conventional chemotherapeutic agents. “None of us is satisfied with the monotherapy results as an end-all,” says Gore. “I’m very interested in combining DNA methyltransferase inhibitors with HDAC inhibitors because, in vitro, that is an effective way of getting silenced genes maximally re-expressed.”
At Celgene, “There’s certainly interest in extending the benefits of Vidaza from the hematological malignancies to solid tumors,” says Backstrom. In addition, Celgene researchers are working on an oral version of azacytidine (Vidaza must be given intravenously or subcutaneously). Oral therapy would offers the potential for prolonged, lower-dose treatments, which could ease side effects.
With all of these great developments, the future looks bright for epigenetic drugs. “The bottom line is that these drugs have finally given hope to people who had no hope,” says Heptinstall. So remember, you could be saving lives, one ChIP assay at a time. (Just do your co-workers a favor, and don’t wear your superhero cape and tights to work on Monday, or ever for that matter.)