Researchers at the UCLA Jonsson Comprehensive Cancer Center have discovered a potential new way to combat pancreatic tumors that express high levels of intratumoral interferon signaling (IFN). The team found that a subset of pancreatic tumors has a high level of IFN type I and triggers a decrease in NAD and NADH levels in pancreatic cancer cells, which are important cofactors in critical metabolic processes.
After describing the mechanism by which NAD depletion occurs, the researchers showed that cells with high IFN signaling are more sensitive to NAMPT inhibitors, which inhibit a major pathway in NAD synthesis. Based on this mechanism, recently developed second generation NAMPT inhibitors could potentially be used in combination with new systemic drugs called STING agonists that increase type I IFN signaling. When tested in mice, the combination of IFN signal and NAMPT inhibitors not only reduced the growth of pancreatic tumors, but also resulted in fewer liver metastases.
“With the advent of these two new and improved therapeutics, our results are timely as their combination can sensitize tumors to NAD depletion,” said lead author Dr. Alexandra Moore, a resident doctor in the surgery department at the David Geffen School of Medicine at UCLA.
Pancreatic cancer remains one of the most difficult cancers to treat. One of the hallmarks of the disease is the extensively reprogrammed metabolic network. All cells, including cancer cells, need to convert nutrients from the environment into building blocks for cellular processes, and many of these processes require NAD or NADH as a vital cofactor. This research focused on the use of IFN-induced NAD depletion in combination with the inhibition of NAD synthesis to develop new approaches for better treatment of pancreatic cancer.
The team first used cell lines and cell cultures to determine the mechanism of IFN signaling-induced NAD depletion by examining the mRNA levels of NAD-consuming enzymes after treatment with IFN. There was an increase in mRNA levels as well as in protein expression of PARP9, PARP10 and PARP14. After confirming the results, the team translated the research into an in vivo model. The researchers used two different models of mice and injected cancer cells into the pancreas of mice prior to treatment.
The results provide evidence that if tumors with high IFN signaling can be identified, or if the IFN signal in tumor cells can be enhanced, then these tumors may be more sensitive to treatment with NAMPT inhibitors. If so, the combination could potentially help improve the prognosis for one of the most difficult cancers to treat.
“This is a study that identifies a potential susceptibility caused by type I IFNs in pancreatic cancer that can be used in what appears to be an effective therapeutic strategy,” said senior author Dr. Timothy Donahue, professor of surgery and chief of surgical oncology.
The research was supported by funding from the National Cancer Institute and the Hirshberg Foundation for Pancreatic Cancer Research.
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