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Epigenetics - Drug Therapy Research

At the Johns Hopkins Kimmel Cancer Center, the first clinical study combining a demethylating agent with histone-blocking HDAC inhibitors was in patients with advanced lung, breast, and colon cancers. 

A Tale of Three Responses

steve baylin Steve Baylin

The drugs were not given at the highest dose that patients could tolerate, as is usually the case in early studies of anti-cancer drugs. Rather, low doses were given. The goal was to kill the cancer cells by reprogramming their DNA, instead of obliterating them like most chemotherapy agents do.  In essence, the researchers, led by Stephen Baylin, M.D., were using the drugs to convert cancer cells back to normal cells—to change their destiny as Dr. Peter Jones of the University of Southern California had done so many years ago in his laboratory studies of 5-azacytidine. 

At high doses, the drug killed cancer cells, but at lower doses over time, it reprogrammed cancer cells to behave like normal cells, a much less toxic and more permanent cancer fix. It was a radical departure from the standard approach of blasting cancer cells with as much poison as possible, but there was significant laboratory evidence to show that it could work.

It did, and remarkably, but only in a few lung cancer patients. The responses, while small in number, were unprecedented. Patients with resistant, lethal lung cancers that had spread to other organs and were resistant to other treatments were seeing their tumors melt away. In a few other patients, tumors stopped growing. Those cancers didn’t go away, but they seemed to be dormant. Grow and spread is what cancer cells do best, so this response, though limited to just a handful of patients, made epigenetics fans and detractors alike take notice.

Still, most patients treated did not respond, and responses in breast cancer and colon cancer patients were not nearly as dramatic as those seen in the small group of lung cancer patients. This did not surprise or deter Dr. Baylin and team. 

Earlier work by his epigenetics colleagues James Herman, M.D., and Malcolm Brock, M.D., showed that specific epigenetic biomarkers provided a signature that could differentiate patients who were likely to respond from those who would not. This trial was open to all patients with resistant cancers, and with no analysis for the epigenetic signature of their tumors, the expectation was that a small subset of patients would see results. The analysis would come later with Dr. Baylin, basic scientist Cynthia Zahnow.

What happened next, however, was not expected. Because of funding provided through Stand Up 2 Cancer, Dr. Baylin and team had the opportunity to do something they typically never would get the chance to do: follow up on patients who were taken off of the trial because their cancers continued to grow despite treatment with the experimental epigenetic therapy. 

The team went back and reviewed these patients’ records, expecting to find that most of them had passed away. These were patients with end-stage cancers that had spread and had not responded to three different attempts at chemotherapy. 

When they learned that many of the lung cancer patients were still alive because their cancers had suddenly begun to respond to a wide variety of anti-cancer drugs, they were shocked. Patients who seemed to progress while they were on the experimental therapy, some who had only received two or three treatments, were alive and doing well. Cancers that had continued to grow and spread despite every effort were suddenly transformed. Such responses were virtually unheard of, and the research team was eager to figure it out.

They pored over every scan, piece of clinical paperwork, and biopsy report available. 

“There could only be two explanations,” says Dr. Baylin. “Either the epigenetic therapy sensitized the cancers to subsequent treatment with standard drugs, or their improvement was a direct response to the epigenetic therapy.” The team needed to complete further studies in the laboratory to solve the mystery.

These new epigenetic targeted therapies do not work like the old cell-killing chemotherapies that do not discriminate between normal cells and cancer cells. They specifically seek out and reprogram the epigenetic alterations that are allowing the cancer cell to survive and grow. 

Dr. Baylin says the epigenetic therapies work slowly over time as they make repairs and return genes to normal function. But Drs. Baylin, Herman, Brock, Ahuja and Zahnow, had another hunch: They suspected that the epigenetic drugs had a priming effect on the tumor. Altering the cancer cell’s gene expression with the demethylating agent and HDAC inhibitor had made the formerly resistant cells now vulnerable to treatment with anti-cancer drugs. 

As they began to study the cell lines in the laboratory, they found that the epigenetic drugs had the capability to impact almost every type of cell mechanism, including cell division, cell repair, and cell cycle and death. Of particular interest to the researchers was the treatment’s effect on genes related to immune response.

Immune cells are on patrol at all times in the human body, differentiating between foreign invaders and normal cells. Cancer cells are derived from normal cells, so they can fly beneath the radar of the immune system. However, as the science of cancer immunology has advanced, researchers are finding that there is more to the cancer cell’s ability to evade the immune system than its similarities to normal cells. 

Cancer cells use epigenetic controls to corrupt immune responses to cancer cells. By hijacking the mechanisms that allow the immune system to differentiate an invading virus cell from a body’s own cells, it causes the immune system to tolerate cancer. 

In their laboratory analyses of gene expression in cell lines derived from patients in the epigenetic treatment studies, one immune target was jumped out at them: a gene called PD-L1.