I've mentioned here before my personal connection to pancreatic cancer, which claimed the life of my grandmother. So I was excited to hear from Stanford cancer researcher Julien Sage, PhD, about some developments on the research front. Sage and postdoctoral scholar Pawal Mazur, PhD, collaborated with Alexander Herner, MD and Jens Svieke, MD, at the Technical University Munich to conduct the work, which was published today in Nature Medicine.
In our release on the study, which was done in animal models, Sage explained:
Pancreatic cancer is one of the most deadly of all human cancers, and its incidence is increasing. 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.
Mazur and Herner worked together to test whether drugs that affect the epigenetic status of a cancer cell (that is, the dynamic arrangement of chemical tags on the DNA and its associated proteins that control how and when genes are expressed) could rein in its growth without serious side effects. Many of these tags are what's called acetyl groups, and they are added to protein complexes called histones that keep the DNA tightly wound in the cell's nucleus. As I explained in our release:
They started by investigating the effect of a small molecule they called JQ1 on the growth of human pancreatic tumor cells in a laboratory dish. JQ1 inhibits a family of proteins responsible for sensing acetyl groups on histones. The researchers found that the cells treated with JQ1 grew more slowly and displayed fewer cancerous traits. The molecule was also able to significantly shrink established pancreatic tumors in mice with the disease. However, it did not significantly affect the animals’ overall likelihood of survival.
Mazur, who began the work in Siveke's lab and continued it when he moved to Sage's lab, next tested whether using JQ1 in combination with any other medications could be more effective:
“It happened that the drug that worked best was another epigenetic drug called vorinostat,” said Sage. “On its own, vorinostat didn’t work very well, but when combined with JQ1 it showed a very strong synergistic effect in both the laboratory mice with pancreatic cancer and in pancreatic cancer cells from people with the disease.”
Vorinostat works by inhibiting a family of proteins that remove the acetyl groups from histones. It has been approved by the FDA for use in people with recurrent or difficult-to-treat cutaneous T cell lymphoma. When human pancreatic cancer cells were treated simultaneously with JQ1 and vorinostat, the cells grew more slowly and were more likely to die.
Mice with established pancreatic cancers treated with both of the drugs showed a marked reduction in tumor size and a significant increase in overall survival time. Their tumors showed no signs of developing a resistance to the treatment, and the mice did not develop any noticeable side effects.
Although much more research needs to be done, the investigators are hopeful that, since vorinostat has already been approved by the Food and Drug Administration, it could be possible to move more quickly than normal to test this drug combination in patients with pancreatic cancer. They also found intriguing hints that the duo may be effective in other types of Ras-driven cancers, including lung adenocarcinoma.
Sage's group is just one of several at Stanford focused on the biology and treatment of pancreatic cancer at Stanford. He and geneticist Monte Winslow, PhD, recently launched a website to catalog the many efforts and enhance collaboration between researchers. As Sage explained to me in a phone call:
Until recently there weren't a lot of people doing basic or preclinical research at Stanford in pancreatic cancer. But now many different groups are working independently on this question, and a number of labs have begun having joint retreats and journal clubs on this topic. We are now nearing a critical mass of people interested in this research, and we hope this website will facilitate interactions among clinicians, researchers and trainees, as well as other outside the university interested in helping us fight pancreatic cancer.
Previously: Peeking into the genome of a deadly cancer pinpoints possible new treatment, Listening in on the Ras pathway identifies new target for cancer therapy and Using CRISPR to investigate pancreatic cancer