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Epigenetics and Combining Drugs

Early but promising results in epigenetics research have transformed the field into a booming industry. Understandably, clinicians wanted to get these promising treatments to their patients. Drug companies want to see if their iteration of epigenetic agents might work even better, and laboratory scientists want to decipher exactly how the drugs are working to combat cancer.  

To confirm findings from a landmark clinical trial giving patients the epigenetic combined therapy of a demethylating agent, histone-blocking HDAC inhibitor and anti-PD-1 treatment, Johns Hopkins Kimmel Cancer Center epigenetics expert Dr. Stephen Baylin knew he must use the same drugs in a subsequent trial. If the team switched the drugs around now, and the results were different, they would never know if variations in outcomes were related to the drugs or epigenetic mechanisms. 

Three different competing drug companies, all with their own versions of the each type of drug and all eager to get them into patient studies, agreed to work together to maintain the integrity of the trial. 

Stand Up 2 Cancer, which had fulfilled a grant commitment to the Epigenetics Dream Team, co-directed by Dr. Baylin, also was eager to see this trial through. After all, the work had achieved SU2C’s goal to rapidly bring new cancer therapies to patients through science and collaboration. Aided by a generous donation from Hollywood agent Jim Toth, whose father died of lung cancer, SU2C extended funding, and study of the three-drug epigenetic therapy is ongoing in patients.

For Dr. Baylin, who is in the front riding the wave, the challenge was managing expectations and waiting for science to reveal the answers.

Cynthia and Steve Cynthia Zahnow and Steve Baylin

There are two components to the trial. One aimed at verifying the immune responses and the other at further testing the priming effect—the ability of epigenetic therapy to sensitize cancers to subsequent chemotherapy. At the same time, a number of trials were being launched at the Kimmel Cancer Center and elsewhere studying a wide variety of epigenetic drug combinations and single agents. Whatever drug or drugs clinical trialists could get their hands on were being studied.

Cynthia Zahnow was gathering the evidence and the data. Collaborating with other Kimmel Cancer Center experts, they had 70 cell lines from breast, colon, ovary, and lung cancers as well as patient biopsies that they were comparing to the cell lines. Gene expression data, methylation data, proteomics data—anything that could be measured in a cancer cell was being analyzed.

“There was still so much we needed to learn,” says Dr. Zahnow. “What is the best way to give the drugs? Should they be given simultaneously or consecutively?  What are all of the targets the drugs hit?”  

There is some evidence that demethylating agents have a stronger effect on the epithelial cells where cancers most often originate. The histone blocking, HDAC inhibitors appear to influence the immune cells and microenvironment.

“We need to figure all of this out so we can better inform drug development and figure out the best way to administer them,” says Dr. Zahnow.

Then there was the aspect of personalized therapy.

 “If everyone’s cancer is different, and each patient has different genes silenced in his or her cancer, then the genes turned back on with epigenetic therapy will be different for each patient,” explains Dr. Zahnow. 

Therefore, the way a demethylating agent, HDAC inhibitor, or immune blockade acts in one patient may likely be different than the way it acts in another patient. 

In the SU2C trials, the three-drug study that includes the anti-PD-1 drug has enrolled the most patients. The priming trial is enrolling patients more slowly, as many are reluctant to gamble with chemotherapy again. They’ve had chemotherapy, and it didn’t work. Their cancers progressed. 

While there is evidence to show that the epigenetic drugs will make some patients’ cancers more sensitive to chemotherapy, most patients want the immune drug. 

“The last thing cancer patients want to hear is that they need more chemotherapy,” says Dr. Zahnow. “If we can get the immune system to function in a way that we could keep a cancer at bay forever, that’s huge. Then we may have a permanent cure,” she says. “Chemotherapy can’t do that. There are always some tumor cells left behind, and they will grow the tumor back.”