Researchers at Washington University School of Medicine in St. Louis have identified an ingredient in a drug that makes pancreatic cancer cells more vulnerable to chemotherapy. While chemotherapy alone (left panel) may cause a certain amount of pancreatic cancer cell death, the compound ATI-450 enhances the effects of chemotherapy (right panel), leading to extensive cell death and disruption of the tumor architecture. Pancreatic cancer cells are shown in green. Red is used to signify dying cells. Dying cells are also highlighted with white Arrows.
It is very difficult to treat pancreatic cancer. When it is detected, the cancer often has reached an advanced stage and patients generally don’t survive for more than one year after diagnosis. While aggressive chemotherapy is the first-line treatment, the side effects can be severe and many tumors stop responding to treatment.
Now, researchers at the Washington University School of Medicine in St. Louis have identified a drug compound that makes pancreatic cancer cells more prone to chemotherapy. They discovered evidence that the drug could also lessen the adverse effects of FOLFIRINOX the chemotherapy mixture consisting of folinic, 5-fluorouracil and Irinotecan, which is commonly used to treat pancreatic cancer.
The study is published on Dec. 1 in the journal Science Translational Medicine.
There is a tremendous need for better and more effective therapies for pancreatic cancer. The current treatments we have are very powerful, but can cause severe side effects , making it difficult to add chemotherapy. This new drug appears to weaken cancer cells and make them more tolerant to this particular treatment. The mice that received chemotherapy in combination with this drug were actually healthier than those who received chemotherapy on their own. This suggests that the new drug may have some negative side effects.
Kian-Huat Liu, MD, PhD Associate Professor of Medicine, senior author and medical oncologist
The anti-inflammatory drug ATI-450 is also being tested in clinical trials for rheumatoid arthritis.
FOLFIRINOX is the first-line treatment for pancreatic cancer, however, only about one-third of patients be able to shrink their tumors after this treatment. This is a temporary response and can last six to seven months. Side effects include nausea, vomiting and diarrhea along with fatigue, hair loss and low blood counts.
The researchers discovered that MK2 is essential in allowing pancreatic cancer cells to survive chemotherapy. This molecule is activated in pancreatic tumor cells. It stimulates signaling pathways that promote survival and reduce cell death. ATI-450, an MK2 inhibitor is a popular option to test against cancerous cells.
“MK2 activates pro-survival mechanisms that allow cancer cells to adapt to the extreme demands of chemotherapy,” said first author and medical oncologist Patrick M. Grierson, MD, PhD, an assistant professor of medicine. “It also blocks the process of cell death called apoptosis which stops cancer cells from dying during chemotherapy. The new drug inhibits MK2 which means that tumor cells are more likely to die when chemotherapy is administered concurrently.
Lim and Grierson both treat patients with pancreatic cancer at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine and their colleagues, tested the drug’s effects in pancreatic cancer cell lines growing in the laboratory, in mice containing pancreatic cancerous human cells and in mice that develop pancreatic cancer naturally due to their genetic predisposition to developing the disease.
Compared with chemotherapy alone, the combination of ATI450 and chemotherapy reduced the size of tumors by about half. The median survival time of mice receiving combination treatment was 41 days in contrast to 28 days for mice who received chemotherapy alone.
“A nearly 50 percent increase in survival rate is an impressive improvement,” Grierson said. It’s impressive that the medication didn’t aggravate adverse effects. The possibility that additional drugs could be added to chemotherapy for pancreatic cancer is a concern. We examined blood counts and analyzed the toxicities of the colon and small intestine which is where we typically see limiting toxicities, and the adverse reactions were not more severe with the combination treatment.”
Lim added Lim: “A lot of the side effects of chemotherapy are caused by inflammation caused by the cytokines. The reduction of cytokines can be an important indicator of success in treating rheumatoid disease, which was the reason behind this drug. It’s possible that we’re seeing the same effect in these mice.”
Researchers are planning to continue their research on ATI-450 for pancreatic cancer. They would also like to know if the drug can be used in combination with chemotherapy. Researchers also noted that the drug has the potential to enhance treatment for other cancers that utilize similar chemotherapy regimens, such as colon cancer and other cancers of the gastrointestinal tract.
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