UCLA Jonsson Comprehensive Cancer Center researchers, including our Scientific Advisory Board member and close collaborator, Dr. Timothy Donahue have uncovered a therapy that subdues tumor growth. The study, published in the prestigious Proceedings of the National Academy of Sciences, was funded by the Hirshberg Foundation the National Cancer Institute. As Dr. Donahue told us, “This project helps us to better understand the biology of pancreatic cancer and how to use that information to develop improved treatment strategies.”
A hallmark of what makes pancreatic cancer so difficult to treat is the tumor’s extensively reprogrammed metabolic network. All cells, including cancer cells, function by transforming nutrients into building blocks for cellular processes. Many of these processes require the critical cofactors NAD and its reduced form, NADH to carry out those processes.
The published research focuses on a subset of pancreatic tumors that express high intratumoral interferon signaling (IFN). The team found that tumors with high type I IFN signaling, trigger a decrease in the level of NAD and NADH in pancreatic cancer cells. The study furthers our understanding of the biology of pancreatic cancer, including the mechanism by which NAD depletion occurs, a vulnerability that can be used in treatment. They showed that NAD and NADH can be further depleted by inhibition of a compensatory enzyme, NAMPT. These chemical cofactors are crucial for cell functions so reducing their availability can decrease tumor growth and disease progression.
The study demonstrated that cells with high type I IFN signaling were more sensitive to NAMPT inhibitors, which inhibit a major pathway in NAD synthesis. The use of NAMPT inhibitors paired with new systemic drugs, called STING agonists, which increase type I IFN signaling, showed not only decreased pancreatic tumor growth, but also resulted in fewer liver metastases.
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 may have greater sensitivity to treatment with NAMPT inhibitors. If so, the combination could provide greater treatment options for pancreatic cancer and improved outcomes. “This project is an example of how continuing to understand the biology of this disease will help us to improve the overall survival.” Dr. Donahue told us.
Funded through the UCLA Agi Hirshberg Center for Pancreatic Diseases, this research builds on the Seed Grant relationship forged in 2009 when the Hirshberg Foundation first funded Dr. Donahue. Senior author of the study, Dr. Timothy Donahue, is the Chief of Surgical Oncology, Program Director of the General Surgery Residency Program and member of the UCLA Agi Hirshberg Center for Pancreatic Diseases. This research was a collaboration with senior author Dr. Caius Radu, Professor of Molecular and Medical Pharmacology, first authors Dr. Alexandra Moore, resident physician in the department of surgery at the David Geffen School of Medicine at UCLA, and Dr. Lei Zhou, a visiting assistant project scientist in the department of surgery.
We applaud the researchers for deepening our understanding of pancreatic cancer biology and moving us another step closer to improved treatment options and ultimately a cure. These interdisciplinary collaborations are crucial for translating research from the bench to the bedside. As Dr. Donahue said, “I am optimistic that therapy for pancreatic cancer will markedly improve in the near future.” Thanks to your support, our momentum is moving us closer to a cure.
Read the UCLA news article →
Read the original research publication →