The new science of epigenetics is leading investigators to innovative methods of treating cancers. And they are doing it using decades-old chemotherapy drugs more successfully and with less toxicity than in the past.
These drugs, including those that target two well-known epigenetic pathways, are already on the market, and new ones are being investigated. Now oncologists are looking at ways to use those drugs in combination or in different doses to make them more effective. They might even be able to overcome failures in solid tumors.
“Epigenetic therapy works. It produces remissions, and it is helping patients live longer, healthier lives with less toxicity,” says Jean-Pierre Issa of University of Texas M. D. Anderson Cancer Center in Houston. “It is a concept that has taken 15 years to develop—the idea of treating cancer not by killing the cells but by changing their gene expression profile. And now in 2006 we can say that this concept is valid and opens a brand-new field of research in cancer therapy in general.”
Understanding Epigenetics
An individual's genome, the DNA sequence of base pairs, is fixed for life and is nearly identical in every cell type in the entire body. But not all genes are on all of the time; certain physical marks on DNA strands can accumulate over time and shut off genes that are supposed to be on. Shutting down tumor suppressor genes and the proteins they express can destabilize the cell cycle, prevent programmed cell death, and lead to uncontrolled proliferation, namely, tumors. Epigenetics examines how and why these genes have been shut down and what could be done to restore normal expression.
Over the last quarter century two theories aim to describe how gene expression could be shut down without changing the DNA sequence. One theory is that the cytosine base in DNA is marked with a methyl group. Tumor tissues are in fact found to be hypermethylated compared with healthy tissues of the same type.
The other theory is that genes are turned off when DNA is too compacted. In its natural state, DNA strands are wrapped around proteins called histones, like thread wrapped around a spool. If DNA is bound too tight, certain genes are silenced. Acetyl groups attached to the histones allow the tumor suppressor genes to function normally. Removing these acetyl groups, called histone deacetylation, can result in tumors.
Two classes of epigenetic drugs are under investigation to treat cancers: DNA methyltransferase (DNMT) inhibitors target DNA hypermethylation, and histone deacetylase (HDAC) inhibitors target histone deacetylation. Some drugs have been around for decades and have been used as chemotherapy for cancers and other disease. The U.S. Food and Drug Administration approved the DNMT inhibitors azacytidine (Vidaza) in 2004 and decitabine (Dacogen) this year, both of which are for myelodysplastic syndromes (MDS). Some weak-acting DNMT inhibitors have also been approved for other indications, such as the local anesthetic procaine (Novocaine) and the antihypertensive hydralazine (Apresoline), but they are not being investigated as epigenetic cancer drugs.
Currently, no HDAC inhibitors are approved for cancers, but suberoylanilide hydroxamic acid, or SAHA (Zolinza), has been submitted as a new-drug application to the FDA for treatment of cutaneous T-cell lymphoma. HDAC inhibitors are approved for diseases other than cancers, including phenylbutyrate (Buphenyl) for urea cycle disorders and valproic acid (Depakote) for seizures; both are being evaluated as potential epigenetic cancer drugs.
From their cell culture work in the lab, many epigenetics investigators believe some of these drugs might work better together than individually. “There's a lot of excitement in combining DNA methylation inhibitors with HDAC inhibitors,” says molecular biologist and oncologist Allen Yang of the University of Southern California's Norris Comprehensive Cancer Center in Los Angeles.
Yang is principal investigator in a multi-institutional phase I/II trial of the HDAC inhibitor MGCD0103 combined with azacitidine in patients with either MDS or acute myelogenous leukemia (AML). He is also interested in the different activity levels of many new HDAC inhibitors coming into clinical trials. “Some have been shown to definitely be synergistic [with DNMT inhibitors] in reactivating gene expression in vitro,” he says. “The assumption is that they will be clinically synergistic also, but the verdict is still out on that.”
A Different Dose
Moving beyond combined drug studies, Issa aims to build on recent clinical results with decitabine by using new schedules and doses in his phase I trial of decitabine and SAHA for “poor-prognosis” hematologic cancers, including MDS and AML.
Issa and his M.D. Anderson colleague Hagop Kantarjian have already tried a different dosing schedule in a recently completed 3-year study using decitabine as a single agent in treatment of MDS and chronic myelomonocytic leukemia. In that study, 69 of 95 treated patients, or 72%, showed some type of response, whereas 32 patients, or 34%, enjoyed disappearance of their disease. Although preliminary, this is a higher response rate than the original phase III trial that led to the approval of decitabine, which demonstrated only 15 of 89 treated patients or 17% getting an overall response, with only eight patients or 9% showing a complete response.
In these trials, Issa randomized patients to three different doses, and the intravenous low dose that was most dose intense showed the highest response rate. Lab tests confirmed that this dose, 25% lower than the decitabine label dose, induced the greatest DNA demethylation. “We saw a clear correlation between gene reactivation and responses, which establishes more proof of principle that we are indeed observing the effect of an epigenetic-acting drug,” Issa says.
Aside from dose, Issa explains that the improved activity is in part because the drug takes more time to work than cytotoxic chemotherapy. Because of the lag, he believes many patients have been undertreated. “[Decitabine] does not act quickly,” he says. “It takes at least 3 months for this repeated hypomethylation to [produce a response], in this case the MDS.”
The low dose story is not new. As early as 1980, USC/Norris molecular biologist and epigenetics pioneer Peter Jones' lab reported that azacytidine wasn't active at higher doses, but investigators did not take this into account in trials. Instead, they went with the traditional test in cancer drug development of a maximum tolerated dose. But Issa wanted to translate Jones' work from the lab to the clinic. He and his colleagues confirmed that at low doses decitabine is an epigenetic-acting drug but it is not as powerful at high doses. “Therefore we needed to redo all the drug development, focusing on methylation and epigenetics as endpoints and focusing on low doses,” says Issa.
Another area of investigation is looking at methylation in a variety of cancers. Kantarjian and his team are expanding research of hypomethylation therapy to lymphoma and several solid tumors. “There are some tumors that are more methylated than others, like colorectal cancer and head and neck cancer and sometimes others like lung and breast cancer,” he says. “So we're trying to target those tumors where methylation is a very notorious event in order to maximize that concept.”
Oncologist and molecular biologist Gregory Otterson at the Ohio State University Comprehensive Cancer Center in Columbus is also doing solid tumor studies. He's close to completing a 10-patient phase I trial with decitabine and the HDAC inhibitor valproic acid for non–small-cell lung cancer. “This is perhaps just the beginning of a different way of therapy,” he says, “just like imatinib [Gleevec] was. These demethylating agents are a different aspect of tumor biology. Decitabine is sort of the tip of the iceberg for that.”
Turning Disappointment Around
Some physicians have expressed disappointment in epigenetic cancer therapies, especially in solid tumors. “I do think epigenetic therapies are promising for the future,” says Ana Aparicio, an M.D. Anderson oncologist and epigenetics researcher. “But I think that the agents that are capable of changing the epigenetic phenotype of a cancer have been disappointing to date because they have not been used as epigenetic therapies, but rather as cytotoxic therapies.”
She said it is critical for physicians to understand the disease biology and the mechanism of action of the drugs under development.
“I would say that many of the physicians using azacytidine and deoxyazacytidine [decitabine] could not explain very well how they are thought to work,” says Steven Gore of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. “And I think the perception of these drugs as being toxic has slowed their move into the clinical armamentarium in a way that's rather surprising, given how toxic most compounds are that these physicians use.”
Steven Gore
