A drug candidate discovered and developed decades ago in the lab of distinguished professor Bruce Hammock at UC Davis could help control the body’s raging and often fatal inflammatory response to chemotherapy treatments, especially for patients with pancreatic and liver cancer.
The research team, based in Dipak Panigrahy’s labs at Harvard Medical School and Hammock, announced the results in Proceedings of the National Academy of Sciences (PNAS) this week.
While working on models of liver and pancreatic cancer in rodents, they found that they could use a combination of two drugs to reduce inflammation after chemotherapy. Inflammation associated with debris from dying tumor cells can trigger metastasis, spreading the cancer throughout the body.
“We have found that we can reduce or eliminate the inflammation generated by chemotherapy by inhibiting or blocking the enzyme, soluble epoxide hydrolase (sEH) and the prostaglandin EP4 receptor,” said co-lead author Hammock, who holds a joint appointment with the UC Davis Department of Entomology and Nematology and Comprehensive Cancer Center.
Basically, when we blocked both the sEH and EP4 eicosanoid pathways, the compounds worked together, preventing pancreatic and liver cancer from metastasizing by stimulating the removal of debris from previous cancer treatment.. “
Dipak Panigrahy, physician-researcher at Israel Deaconess Medical Center, Harvard School of Medicine
The EP4 antagonist INV-1120 is currently in a Phase I clinical trial in the United States, said co-author Yongkui Sun, president of Ionova Life Science, a biotechnology company in China that translates the findings of basic biomedical research into de new cancer therapies.
Control inflammation upstream
In the preclinical animal model, INV-1120 has been shown to synergize with anti-PD-1, the sEH inhibitor, in the fight against cancers such as pancreatic and liver cancers, Sun said. .
The sEH and EP4 proteins play an important role in promoting inflammation. Hammock discovered the sEH pathway decades ago while researching metamorphosis in butterflies. The sEH pathway has been shown to be important in both pain and inflammation in humans. Hammock founded UC Davis-based EicOsis Human Health LLC to bring the sEH inhibitor to human clinical trials now underway in Texas.
âControlling the body’s inflammatory response to chemotherapy will likely be important in preventing metastasis,â Hammock said. “It struck me that what we really need to do is not so much to block the cytokines as to go upstream to modulate them and resolve them rather than block the inflammation.”
Combining drugs to block the sEH and EP4 pathways is a new approach to reduce inflammation and prevent the cytokine storm caused by chemotherapy and even tumor resection, the authors said.