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Pancreatic cancer is one of the types of more aggressive and deadly tumors and is known for his resistance to virtually all types of treatment, including the newer immunotherapies.
Now, a new study conducted on mice by a team from the Faculty of Medicine of the
Washington University in St. Louis (USA) suggests that blocking an important inflammatory pathway that is activated in pancreatic cancer makes tumors sensitive to chemotherapy and a type of immunotherapy that prompts the immune system’s T cells to attack cancer cells. The therapy more than doubled survival in a mouse model of pancreatic cancer.
The results of the study, published today in the journal
«Gastroenterology»provide additional support for the rationale for a new national clinical trial that will evaluate the same treatment strategy in patients with pancreatic ductal adenocarcinoma, the most common malignant tumor of the pancreas.
The researchers plan to enroll about 50 patients across the US.
“With this therapy, we look for a pathway that we know is involved in boost aggressiveness of cancer pancreas,” says lead author Kian-Huat Lim.
The results of this study are promising because they showed a way to break down the defenses of this type of tumor, making it susceptible to our therapies, including combinations of chemotherapy and immunotherapies newer ones that stimulate T cells to fight cancer,” says lead author Kian-Huat Lim.
The researchers found that a protein called IRAK4 causes inflammation in pancreatic tumors and leads to T-cell depletion, which means T-cells can’t function as they should to attack harmful cells, including cancer.
The study tested an IRAK4 inhibitor, called CA-4948, and found that the treatment reduced the inflammatory signaling in tumors in mice and enhanced the ability of T cells to infiltrate tumors and kill pancreatic cancer cells. The therapy also sensitized tumors to a type of immunotherapy called checkpoint immunotherapy, which “takes the brakes off” T cells, enhancing their ability to attack tumor cells.
The researchers found that the IRAK4 inhibitor shuts down a key pathway called NF-kappaBwhich has long been known for its role in cancer progression.
Much of the research focuses on shutting down this pathway and its downstream effects after it is activated. A novel element of this therapy is that the IRAK4 inhibitor prevents the harmful pathway from being activated in the first place.
In mice with a common aggressive model of pancreatic cancer, the researchers found that the IRAK4 inhibitor it only increased survival compared to a placebo or chemotherapy.
However, the combination of the IRAK4 inhibitor plus chemotherapy further increased survival compared to the placebo o la chemotherapy alone.
Furthermore, when combined with two immunotherapies, the IRAK4 inhibitor significantly prolonged the survival of an average of 25 days with the inhibitor alone to an average of 46 days with the combination of inhibitor plus immunotherapy. Some of the mice survived up to 100 days on the combination therapy.
The IRAK4 inhibitor is already in national clinical trials investigating its use against blood cancers.
“We hope to start the test national clinical of this drug in patients with pancreatic cancer; the essay is a direct translation of this particular article,” adds Haeseong Park.