A combination of two drugs, one already approved by the Food and Drug Administration, appears to be effective at shrinking pancreatic cancers in laboratory mice, according to a new study published in Nature Medicine. The drugs, which affect the structure and function of the cancer cell's DNA rather than the activity of its proteins, also slowed the growth of human lung cancer cells in mice.
The researchers wondered whether tinkering with a cell's epigenetics could control the growth and proliferation of pancreatic cancer cells without causing the side effects seen by drugs that inhibit protein members of the Ras pathway.
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. 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.
When the researchers investigated the effect of JQ1 treatment more thoroughly, they found that it inhibited the expression of a gene called Myc, which is known to be associated with many types of cancers, including pancreatic cancer. It also decreased the levels of inflammatory molecules known to be involved in the development of pancreatic cancer.
"The effect of JQ1 treatment was OK, but not amazing," the researchers said. They decided to look for drug combination that might have a synergistic effect, and tried eight drugs each targeting either a known cancer-associated pathway or a step involved in epigenetics.
The drug that worked best together with JQ1 was vorinostat. 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.
Finally, Mazur tested the effect of the combination treatment on a type of lung cancer that, like pancreatic cancer, is driven by mutations in KRAS. He found that together JQ1 and vorinostat also significantly increased the survival of mice with this cancer, called lung adenocarcinoma.
The researchers hope this newly identified combination treatment can be tested in the clinic within the next five years. The fact that vorinostat is already approved for use in humans may speed the process, they believe. They're also interested in learning whether the treatment may be effective in other types of conditions.
Based on material originally posted by Stanford University Medical Center.