The chemo cocktail known as folfirinox is the go-to treatment for pancreatic cancer, but it works in only about 30% of patients, and those responders eventually relapse. Scientists at Washington University School of Medicine in St. Louis set out to find a way to make pancreatic cancer more amenable to chemo—and they found it in an unexpected place.
The team discovered that Aclaris Therapeutics’ experimental rheumatoid arthritis drug, ATI-450, boosted the ability of folfirinox to kill pancreatic cancer cells. In mouse models of the disease, the combo shrank tumors and improved survival, they reported in the journal Science Translational Medicine.
The key to ATI-450’s effectiveness in pancreatic cancer is its target, MAPK-activated protein kinase 2 (MK2), the Washington University researchers discovered. Their research demonstrated that MK2 shields pancreatic cancer cells from chemotherapy by allowing them to adapt to stress and preventing programmed cell death, or apoptosis. ATI-450 was designed to inhibit MK2.
The researchers tested ATI-450 in pancreatic cell lines, mice with human pancreatic tumors and mice that developed the disease because of a genetic predisposition.
In the animals, combining ATI-450 with chemo shrank tumors by about 50% and improved survival from 28 days in those receiving chemo alone to 41 days, the researchers reported.
What’s more, the combination treatment didn’t worsen the side effects of chemo, they said. “In fact, the mice treated with chemotherapy plus this drug appear to be healthier than mice receiving chemotherapy alone, so there’s a chance [ATI-450] is mitigating side effects,” said senior author Kian-Huat Lim, M.D., Ph.D., associate professor of medicine at Washington University, in a statement.
During the experiment, Lim’s team monitored the blood, small intestines and colons of the mice and found that adding ATI-450 to chemo did not increase treatment-limiting toxicities over chemo alone. That may be because the drug tamps down inflammatory cytokines, which are not only a major culprit in RA, but are also responsible for many of the side effects of chemotherapy, Lim said.
Given that pancreatic cancer is one of the toughest forms of the disease to treat, there is high interest among oncology researchers in finding innovative combinations to improve the prognosis for patients. BioXcel Therapeutics collaborated with scientists at Georgetown University to test a combination of its failed pancreatic cancer drug candidate, talabostat, along with PD-1 inhibitors, for example. Last month, the research team announced positive preclinical data on the combination. Talabostat inhibits the protein dipeptidyl peptidase (DPP).
Apexigen is testing a combination of PD-1 inhibition with its CD40-activating antibody in pancreatic cancer, turning out promising results from an early clinical trial. And last year, a team at Boston Children’s Hospital announced that when they combined an antibody-drug conjugate (ADC) that binds to a molecule on pancreatic cancer cells called ICAM1 with the existing anti-cancer drug DM1, it shrank tumors and prevented metastasis in mouse models of pancreatic cancer.
As for Aclaris, it has endured a fair share of struggles over the past few years. In 2019, its drug candidate for alopecia failed a mid-stage study, prompting the company to pivot its resources to developing ATI-450 and other drugs to treat inflammatory diseases. In January of this year, the company’s stock soared on news that ATI-450 produced promising results in a phase 2 study in RA.
The Aclaris-WashU team plans to investigate whether ATI-450 could be combined both with both chemotherapy and immunotherapy in pancreatic cancer, and they’ve filed for a patent based on their work so far, according to the statement.