Epigenomic combo shows promise in mouse model of pancreatic cancer

Stanford's Julien Sage

Researchers at Stanford University School of Medicine have found that combining two drugs that target the epigenome of cancer cells may be effective in killing off pancreatic tumor cells.

The two senior authors, Julien Sage and Dr. Jens Siveke (Technical University of Munich), bring together their labs' expertise in cancer genetics to publish in Nature Medicine ahead of print earlier this week.

"Pancreatic cancer is one of the most deadly of all human cancers, and its incidence is increasing," said Sage. "Nearly always the cause of the disease seems to be a mutation in a gene called KRAS, which makes a protein that is essential for many cellular functions. Although this protein, and others that work with it in the Ras pathway, would appear to be a perfect target for therapy, drugs that block their effect often have severe side effects that limit their effectiveness. So we decided to investigate drugs that affect the DNA rather than the proteins."

The collaborative effort had initially looked at a small molecule called JQ1--previously shown by others to have an important anticancer mechanism. JQ1 inhibits a family of histone protein "readers" and specifically a BET-family member called BRD4. By preventing the normal function of BRD4 to recognize acetyl groups on histone proteins, the result is the condensing of chromatin which prevents aberrant gene expression within cancerous cells.

In particular they looked at JQ1 in human pancreatic tumor cells and found that cells grew more slowly following treatment with this drug. This was replicated in a mouse model of pancreatic cancer treated with JQ1, and this led to reasoning that Myc expression was being prevented--a gene that becomes overactive in many cancers.

JQ1 also reduced the levels of inflammatory molecules that are typically seen in pancreatic cancer. However, the effects of JQ1 although mechanistically promising didn't change the survival rate in the mouse model of pancreatic cancer. This spurred the researchers to find combination therapy to use alongside JQ1.

After testing a panel of epigenetic drugs or ones that are known to hit the cancer pathways, they found vorinostat, which on its own has little effect--yet in combination with JQ1 had very strong synergistic effects.

By using the popular CRISPR technique to cut out important regulators in their pathway, they deduced that the combination therapy works by increasing p57 which blocks cells from dividing and has been previously noted for being protective against cancers.  

Since vorinostat is FDA approved, the team will only have to see the combination therapy of vorinostat-JQ1 pass through clinical trials. They remain hopeful that in 5 years it will be being tested in the clinic.

"We don't know yet whether this synergistic effect is specific to cancers driven by mutations in KRAS or if it could also work on other types of cancers," Sage said.

- here's the release
- get the research abstract