In pursuit of pancreatic cancer

Study finds combination therapy with NAMPT inhibitors and STING agonists can suppress pancreatic tumor growth in mice

Register for free to listen to this article
Listen with Speechify
In pursuit of pancreatic cancer

LOS ANGELES—Researchers at the UCLA Jonsson Comprehensive Cancer Center may have uncovered a new way to target pancreatic tumors that express high intratumoral interferon signaling (IFN). A study, published in Proceedings of the National Academy of Sciences, found that high type I IFN signaling is present in a subset of pancreatic tumors and triggers a decrease in the level of NAD and NADH in pancreatic cancer cells, which are vital cofactors in critical metabolic processes.

“Emerging evidence suggests that intratumoral interferon signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors,” says the article abstract. “Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14.”

The team defined the mechanism underlying NAD depletion, and demonstrated that cells with high IFN signaling were more sensitive to nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which inhibit a major pathway in NAD synthesis. Researchers believe that NAMPT inhibitors could potentially be used in combination with STING agonists, which increase type I IFN signaling. When tested in mice, the combination of IFN signaling and NAMPT inhibitors decreased pancreatic tumor growth, and resulted in fewer liver metastases as well.

“With the advent of these two new and improved therapeutics, our findings are timely as their combination may sensitize tumors to NAD depletion,” explained Dr. Alexandra Moore, a resident physician in the department of surgery at the David Geffen School of Medicine at UCLA, and a lead author of the study.

One of the hallmarks of pancreatic cancer is its extensively reprogrammed metabolic network. All cells — including cancer cells — have the need to transform 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 harnessing IFN-induced NAD depletion, in combination with the inhibition of NAD synthesis, to hopefully develop new approaches that can better treat pancreatic cancer.

The researchers first used cell lines and cell culture to determine the mechanism of NAD depletion induced by IFN signaling by looking at the mRNA levels of NAD-consuming enzymes after treatment with IFN. There was an increase in mRNA levels, as well as protein expression of PARP9, PARP10, and PARP14. After confirming the findings, the team translated the research into an in vivo model. The team used two different mouse models, and injected cancer cells into the pancreases of mice prior to treatment.

“We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition," added the article. "Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.” 

“This is a study that identifies a potential vulnerability created by type I IFNs in pancreatic cancer that can be leveraged for what appears to be an effective therapeutic strategy,” noted senior author Dr. Timothy Donahue, professor of surgery and chief of surgical oncology, and a senior author of the study.

The findings provide evidence that if tumors with high IFN signaling can be identified — or if IFN signaling can be amplified in tumor cells — those tumors could have greater sensitivity to treatment with NAMPT inhibitors. And if so, the combination of NAMPT inhibitors and STING agonists could improve the prognosis for pancreatic cancer.

Subscribe to Newsletter
Subscribe to our eNewsletters

Stay connected with all of the latest from Drug Discovery News.

DDN Magazine May 2024

Latest Issue  

• Volume 20 • Issue 3 • May 2024

May 2024

May 2024 Issue