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In applying cancer gene discoveries to treatment, investigators are focusing on the pathways through which altered cancer genes work because the genes themselves can often be elusive to therapy. Many of the gene mutations driving cancers are in tumor suppressor genes. The loss of these genes removes important brakes on cell growth, but it’s difficult to attack a target that’s already missing.
Sometimes, however, tumor suppressor genes become ineffective without being mutated. The causes of this are known as epigenetic alterations. Biochemical changes to the environment of the DNA, rather than directly to it, can silence key genes. Investigators have found that using drugs to block this biochemical activity provides an opportunity to reverse the changes and reset the DNA to its pre-cancer environment.
Kimmel Cancer Center researcher Stephen Baylin is to the field of cancer epigenetics what Bert Vogelstein is to cancer genetics. He, and colleague Jim Herman, are the leading experts on the topic, cited more frequently than any other researchers in the field. Their epigenetic work in lung cancer earned Baylin recognition from the National Cancer Institute for the most outstanding research in its SPORE (specialized programs of research excellence) program, an endeavor aimed at rapidly moving research discoveries to patient care.
Baylin began his work in the 1980s when he noticed regions of genes with increased methylation, a biochemical process that seemed to occur only in cancer cells. This chemical change, he found, was like an off switch to tumor suppressor genes. With support from the Commonwealth Fund, Ludwig Foundation, Hodson Trust, and the National Institutes of Health, he and his team began to look for ways to apply these observations to cancer patients.
Early laboratory studies in lung cancer and leukemia at the Kimmel Cancer Center and elsewhere led recently to clinical trials of the first demethylating agent, 5-azacytidine. Promising results in a leukemia and a pre-leukemia condition known as myelodysplastic syndrome (MDS) resulted in FDA approval of the drug for MDS. Now, they are working to prove the effectiveness of the drug in other cancers.
Their research has led them to other changes working in concert with methylation, specifically something known as the chromatin structure.
Chromatin is a complex combination of DNA and proteins, mainly histones. Its job is to compress DNA to make it fit inside cells, providing a mechanism for controlling gene expression and DNA replication. Changes in the structure of chromatin are controlled by the histones. A loose chromatin allows for normal gene expression. But, add methylation to the equation and histones hold DNA together tightly interfering with the normal expression of genes, including tumor suppressor genes. It keeps genes in a constant state of non-expression.
Prior to this discovery, most investigators studying cancer genes looked at gene silencing as a linear process across the DNA, as if genes were flat, one dimensional objects. Research did not take into account the way genes are packaged.
For a key set of tumor suppressor genes, this packaging can cause cells to behave in a primitive, embryonic cell-like fashion. Unlike true embryonic cells which receive and respond to signals to stop making copies of themselves, cancer cells maintain their ability to replicate, renew, and divide. The cells never receive the command to stop dividing partly because abnormal DNA methylation has silenced the key growth-limiting signals. “Chromatin is held in a tight, compressed form, particularly when associated with DNA methylation,” says Baylin. “These tighter coils and loops touch and interact with many gene sites, folding it into a structure that shuts off tumor suppressor genes,” says Baylin.
When the researchers removed DNA methylation from the genes, using a combination of 5-azacytidine and a drug known as a HDAC inhibitor for its ability to block histones, the coils loosened, and some gene expression was restored.
What prompts the cancer-promoting changes in chromatin structure is unknown. Baylin suspects some of it is due to continued environmental assaults to the cells, such as chronic inflammation. As cells try to renew and repair over and over, something breaks, epigenetic alterations accumulate, and some cells become locked in this primitive state. As a result, these cells learn to live outside the context of their normal environment and begin to expand autonomously outside the limits of normal cell control mechanisms.
With funding from Stand Up To Cancer, Baylin and team have now moved their laboratory discoveries to the clinic in studies with lung, breast, and colon cancer patients. Learning from the earlier clinical trials in leukemia, the new patient studies combine the DNA demethylating agent 5-azacytidine with histone-specific HDAC inhibitors to target both abnormal methylation of genes and the alterations to DNA packaging that help give cancer cells their edge.
It is a novel concept. Rather than attacking and destroying replicating cells as standard chemotherapy drugs do, this therapy actually aims to reprogram cells to behave more like normal cells. Clinical responses in lung cancer patients that have lasted long after treatment has ended indicate that it’s working. It’s too early in the breast and colon cancer trials to evaluate, but Baylin and team are optimistic that they will see favorable results in these cancers as well.
Using drugs that specifically target the abnormal mechanisms, allows the investigators to give patients lower doses and still maintain effectiveness. They believe the lower doses allow them to hit the epigenetic target without interfering with the activity of other non-target genes. As a result collateral damage to normal cells has been low, with relatively mild and few side effects, including fatigue, minor decreases in blood counts, and irritation at the injection site.
It is a striking contrast to high-dose studies of the drug in the 70s and 80s when it was all but abandoned because it was too toxic. “We reduced the dose and added an HDAC inhibitor and are working to prove in clinical trials what we already suspect; that the combination of the two drugs is safe and works better than either individually,” says Baylin.
In early clinical trials, clinician-scientists Charles Rudin and Rosalyn Juergens are having remarkable success in lung cancer patients. Patients who had failed at least three attempts with standard chemotherapy are getting results. “We are even seeing responses to metastatic disease. Lesions in the liver, where the lung cancer had spread, are disappearing,” says Baylin. “We are not saying cure, but these are lasting regressions of the worst stage of disease. So, maybe we are at a place where we are beginning to control even the most difficult cancers.”
Baylin and team are now ready to move the therapy to earlier-stage patients, just after surgery to prevent cancer recurrence.