Breaking the Silence: The Rise of Epigenetic Therapy

Cancer epigenetics is hot. At the annual meeting of the American Association for Cancer Research in April, once-obscure principal investigators were feted by gaggles of admirers and many poster presenters mobbed by the curious. “It’s one of the hottest areas of basic biology,” said Paul Workman, Ph.D., director of cancer therapeutics at Cancer Research U.K. in Sutton, England. Workman said he believes that epigenetic gene silencing is as much a driving force in cancer as genetic mutation. “This is just a major, major way in which tumors turn off genes they don’t want expressed,” he said. This statement would have been heresy just a few years ago, but most scientists now accept that remodeling of chromatin is central to cancer. Chromatin consists of proteins called histones, which form nucleosome beads looped and linked by DNA. Methylation and histone deacetylation function to bind DNA tightly to histones and prevent the transcription and expression of tumor suppressor genes. (See News, June 5, p. 793.) Reverse this process by relaxing chromatin, the theory goes, and gene expression will drive cancer cells to commit suicide or to senesce. Researchers are testing this theory with methylation inhibitors and histone deacetylase (HDAC) inhibitors. HDAC inhibitors are generating the most excitement. In the late 1990s, studies in various leukemias implicated HDACs in the inappropriate silencing of tumor suppressor genes. In 1999 the NCI began human trials of Fujisawa Pharmaceuticals’ depsipeptide, a natural product that had shown activity in the National Cancer Institute’s standard 60-cell line screen before it was discovered to be an HDAC inhibitor. Results in patients with certain subtypes of T-cell lymphoma have so far been spectacular. “The majority of patients respond to it, and respond dramatically,” said NCI senior investigator Susan Bates, M.D. “We’ve had patients go from very large tumors all over their body, to nothing. Some of these responses are durable, but it’s not the magic bullet—tumors do become drug resistant and tumors do come back.” Bates hopes to eventually combine the drug with inhibitors of multidrug resistance such as P-glycoprotein inhibitors. In the meantime, the NCI is enrolling T-cell lymphoma patients in an expanded depsipeptide trial. “I’ve had many years of drugs that haven’t worked at all, so it’s amazing,” said Bates. “It has the potential to work very, very well.” A new compound, SAHA (suberoylanilide hydroxamic acid), is attracting even more attention. Synthesized as a more potent derivative of an old differentiation agent that Memorial Sloan-Kettering’s Paul Marks, M.D., tried in the clinic with limited success, SAHA was found in 1998 to be an HDAC inhibitor. Marks, Victoria Rishon, Ph.D., and two colleagues recently founded a company, Aton Pharma, to bring SAHA to market. At AACR, Marks reported that, in a phase I trial, the drug demonstrated safety, inhibited its target enzyme, and led to “tumor shrinkage” in four bladder cancer and lymphoma patients. HDAC inhibitors are exciting in part because they offer a kind of pharmaceutical shortcut to selectively reactivating tumor suppressor genes. “We now have a way of switching genes on and off,” said Aton chief executive officer Nick Bacopoulos, Ph.D. SAHA, for example, induces expression of the p21 tumor suppressor gene, among others. At the same time, the drug is not causing havoc in the cell by remodeling chromatin everywhere, as many predicted HDAC inhibitors would. According to Aton’s microarray expression studies, SAHA alters expression of fewer than 2% of all genes. But why there is a specific anticancer effect remains unknown. “For some reason, there’s a selective advantage in cancer cells,” said Bacopoulos. “You remove it, they don’t grow and they die, whereas normal cells can bypass whatever you’ve done to the cancer cells. In a way, the proof is in the pudding, and all our speculations will have to be tested experimentally.” Depsipeptide and SAHA are the tip of the iceberg. “There’s a whole slew of HDAC inhibitors in preclinical and clinical development,” said Workman. Cancer Research U.K., for example, has a Novartis HDAC inhibitor, LAQ824, in clinical trials. MethylGene, a Montreal biotech company, is preparing its own HDAC inhibitors for the clinic, and is also analyzing the separate roles of the 11 known HDACs in cancer. That’s crucial for target selection, but nothing is yet known publicly. “We’re reluctant to divulge that because the competition is so hot. There [are] so many big pharma players,” said MethylGene director of biology Rob MacLeod, Ph.D. MethylGene also has drugs that inhibit DNA methylation. In simplistic terms, methylation silences genes while acetylation activates them, so drugs affecting either process should work against cancer. This has not always been obvious. The enzymes that catalyze methylation—DNA methyltransferases—have been known for more than a decade, but because global hypomethylation is a hallmark of many tumors, few thought that reversing hypermethylation (often found in the promoter regions of tumor suppressor genes) would do any good. MethylGene founder Moshe Szyf, Ph.D., of McGill University, was among the first to propose that inhibiting methyltransferases might work as a cancer treatment. MethylGene’s antisense methyltransferase inhibitor, MG98, is deep into multiple phase II clinical trials for a variety of cancers. Phase I results showed safety and some evidence of efficacy. To improve potency and specificity, MethylGene is now developing small molecule inhibitors of the three DNA methyltranferases. But can methylation inhibitors be safe? Global reversal of gene silencing at first glance seems likely to set off a tidal wave of gene expression lethal to normal cells. But methylation of promoter CpG islands apparently is not a common way of controlling gene expression in normal cells, and so far demethylating agents have not shown massive toxicity in patients. One of these agents is decitabine (5-aza-deoxycytidine), a powerful methylation inhibitor first synthesized in Czechoslovakia in the 1960s. Pharmacologist Richard Momparler, Ph.D., of the University of Montreal, has been championing the drug for more than 20 years. With scant or nonexistent grant support, Momparler has undertaken several human trials. Now, thanks to all the new interest in methylation, Momparler has launched a new lung cancer trial using a new dosing regimen. “The full potential [of decitabine] has yet to be realized,” he maintained. With Dublin, Calif.-based biotech company SuperGen sponsoring several such trials, decitabine is enjoying a revival. Jean-Pierre Issa, M.D., of the University of Texas M. D. Anderson Cancer Center, gives a decitabine dose many times lower than Momparler’s, to great effect and with much lower toxicity. In phase I studies, “a little more than half of the patients at the optimal [low] dose responded,” Issa reported, cautioning that these dramatic results need confirmation in phase II. He has now proposed a trial of low-dose decitabine in chronic myelogenous leukemia (CML) for patients who do not respond to Gleevec, because methylation is thought to play a role in progression of the disease to blast crisis, CML’s invariably fatal end stage. Better methylation inhibitors are on the way. “The one problem with methylation inhibitors [is that] when you remove the drug, the gene goes back off again,” said Peter Jones, Ph.D., director of the University of Southern California Norris Comprehensive Cancer Center. “You’re going to need therapy over a long period of time.” Jones and others are looking for compounds that are nontoxic enough to give continuously. Jones, Issa, and virtually everyone else working with these drugs say that an obvious next step is to use HDAC inhibitors and methylation inhibitors together. “If you combine an HDAC inhibitor with a DNA methylase inhibitor, you get this very powerful synergy,” said Workman. A few such trials may soon begin, although drug companies are reluctant. “Clinical trials with two experimental agents don’t usually lead to approval of a drug by the [Food and Drug Administration],” Issa observed. “It’s a hurdle.” In the meantime, companies are working frantically to get their epigenetic drugs into the clinic before the competition. “It’s a little bit like where we were with kinase inhibitors several years ago,” said Workman. “It’s inevitable that everyone is going to dive into this area now.” Dr. Paul Workman Some Epigenetic Therapies in the Clinic Some Epigenetic Therapies in the Clinic

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