Combining the current standard-of-care chemotherapy drug with a genetic inhibitor may improve treatment for pancreatic ductal adenocarcinoma (PDAC), according to a Northwestern Medicine study published in Proceedings of the National Academy of the Sciences (PNAS).
There are currently no targeted treatments for PDAC and chemotherapy comes with a host of side effects, so this combination drug strategy is promising, according to Mazhar Adli, PhD, associate professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine and senior author of the study.
“The hope is that we will use less of the chemotherapy drug because those drugs are very toxic, and that we will find a drug combination that specifically targets cancer cells, sparing normal cells and achieving synergistic cell death,” said Adli, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
PDAC is an extremely difficult cancer to detect and treat. Symptoms typically do not develop until the cancer has reached an advanced stage and most patients are not eligible for surgical resection because of the cancer’s spread and its proximity to major blood vessels.
For patients who are ineligible for surgery, the normal standard of care is a chemotherapy drug called gemcitabine. However, PDAC often resides deep within fibrotic tissue and greatly interferes with normal pancreatic functions, such as releasing hormones for blood sugar levels and secreting digestive enzymes for food processing.
These factors contribute to a high mortality rate that persists even as new and more effective treatments have been developed for other cancers, according to Adli.
“Every year, about forty-five thousand people are dying from this cancer, and that rate of death is still growing,” Adli said.
Rather than searching for a new drug, Adli and his collaborators set out to find a companion drug that could make gemcitabine more effective. The investigators performed an unbiased screen of thousands of genes, searching for the one whose depletion will make cancer cells more sensitive to gemcitabine.
This unbiased screening identified a gene called PRMT5. They found that patients who expressed high levels of PRMT5 — an epigenetic regulator that makes certain genes less likely to be expressed — had worse outcomes than patients without high levels of the protein. Likewise, PDAC tumor cells also expressed high levels of this protein.
“These two together told us that this was a promising gene to inhibit,” Adli said.
The scientists then embarked on a multi-stage test: they deleted the gene using CRISPR-Cas9 editing in cell models of PDAC, while at the same time applying a pharmacological inhibitor of PRMT5 in a separate group of models. Once the gene was suppressed, they delivered gemcitabine and found that the chemotherapy drug was drastically more effective at killing cancer cells compared to models where PRMT5 was intact.
They repeated this two-track experiment using mouse models of PDAC, with similarly encouraging results.
PRMT5 has been linked to other cancers, and there are two clinical-grade inhibitor drugs that are being tested in clinical trials. But, Adli said he believes the combination of gemcitabine and these inhibitors would be a much more effective therapy than the inhibitors or gemcitabine alone.
“Pancreatic cancer patients are desperately awaiting a new drug combination,” Adli said. “We are hoping that we can initiate a clinical trial in collaboration with these drug companies as soon as possible.”
Harun Ozturk, a second-year student in the Driskill Graduate Program in Life Sciences (DGP), was a co-author of the study.
The study was initially funded by a pilot project award from the University of Virginia Cancer Center and through the National Cancer Center (NCI) Support Grant 5P30CA044579, the Pinn Scholar Award and from National Institutes of Health/NCI grants R01 CA211648-01 and R01 CA060499.