As one of the leading causes of cancer-related deaths in the U.S., pancreatic cancer represents a major threat to public health. This year, about 55,000 people in the U.S. will be diagnosed with the disease and more than 44,000 will die, making it one of the deadliest cancers. Currently, the pancreatic cancer five-year survival rate is only 7% and drugs to treat this aggressive disease are limited and many ineffectual.
However now, investigators from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai may have found a reason to be hopeful as results from their new study show that a newly developed drug called Meavert, can prevent the most common type of pancreatic cancer from growing and spreading in laboratory mice. The findings from this new study—published recently in Gastroenterology through an article titled “An Inhibitor of GSK3B and HDACs Kills Pancreatic Cancer Cells and Slows Pancreatic Tumor Growth and Metastasis in Mice”—also demonstrated that Metavert could prevent patients from developing a resistance to currently used pancreatic cancer chemotherapies.
“This is an exciting step toward improving survival rates in pancreatic cancer patients,” explains lead study investigator Mouad Edderkaoui, Ph.D., assistant professor of medicine and biomedical sciences at Cedars-Sinai. “If the results are confirmed in humans, we could have a drug with the potential to significantly extend the lives of patients with pancreatic ductal adenocarcinoma (PDAC), which is very difficult to treat.”
Ninety-five percent of pancreatic cancer patients are diagnosed with PDAC, which develops from cells lining small tubes in the pancreas. PDAC can be difficult to treat because the cancer cells prompt normal cells that reside in the pancreas—called stellate cells—to produce pancreatic scar tissue. Scar tissue makes it difficult for chemotherapy agents and blood to enter the pancreas.
The cancer and stellate cell interaction also create an environment that stimulates local tumor growth, and cancer spread to distant sites in the body. Additionally, the activity levels of certain enzymes rev up, fueling resistance to cancer treatments.
“Metavert significantly reduced survival of PDAC cells but not nontransformed cells; the agent reduced markers of the epithelial to mesenchymal transition and stem cells in PDAC cell lines,” the authors wrote. “Cells incubated with metavert in combination with irradiation and paclitaxel or gemcitabine had reduced survival compared to cells incubated with either agent alone; metavert increased killing of drug-resistant PDAC cells by paclitaxel and gemcitabine. PDAC cells incubated with metavert acquired normalized glucose metabolism. Administration of metavert (alone or in combination with gemcitabine) to KPC mice or mice with syngeneic tumors significantly increased their survival times, slowed tumor growth, prevented tumor metastasis, decreased tumor infiltration by tumor-associated macrophages, and decreased blood levels of cytokines.”
Over a four-year period, the investigators designed and synthesized new chemicals that inhibit cancer cell activity. They discovered that Metavert blocked drug resistance and also significantly boosted the positive effects of radiation and two chemotherapy agents commonly used in humans. In one of the mouse studies, Metavert increased the survival rate by about 50%.
“I've seen patients who respond to therapy for a while, and then the disease takes off because the cancer becomes smart—it blocks chemotherapy from working,” notes senior study investigator Stephen Pandol, M.D., director of basic and translational pancreas research at Cedars-Sinai. “Metavert targets that action.”
The authors concluded that “in studies of PDAC cells and two mouse models of PDAC, we found a dual inhibitor of GSK3B and HDACS (metavert) to induce cancer cell apoptosis, reduce migration and expression of stem cell markers, and slow growth of tumors and metastases. Metavert had synergistic effects with gemcitabine.”
Currently, the Cedars-Sinai group is working to develop a version of the drug to test in humans.