Research led by scientists at the Jonsson Comprehensive Cancer Center (JCCC) at UCLA provides new insights into molecular “crosstalk” in pancreas cancer cells, identifying vulnerabilities that could provide a target for therapeutic drugs already being studied in several cancers. This interdisciplinary research was led by a team of JCCC investigators, Caius Radu, MD, an expert in cancer cell metabolism, and Timothy Donahue, MD, a pancreas cancer surgeon and an expert in pancreas cancer biology.

“Pancreatic ductal adenocarcinoma (PDAC), which is highly resistant to current therapies, is expected to become the second most common cause of cancer-related deaths in the United States within this decade,” said the paper’s senior author Radu, a researcher at Jonsson Comprehensive Cancer Center at UCLA and Professor in the Department of Molecular and Medical Pharmacology at UCLA.

Caius Radu, MD. UCLA assistant professor of molecular and medical pharmacology and a Jonsson Cancer Center researcher.

“Results of this study increase our understanding of the inflammatory microenvironment within these tumors and suggest targeted pharmacological strategies that could be employed to leverage this hallmark feature of pancreas cancer by current treatments,” Radu further noted.

The preclinical research, using tumor cells from patients and cell line-derived xenograft tumors, was published online at Cell Reports on January 11, 2022. It centers on STING-driven type I interferon, an immune system signaling molecule that impairs cancer cell proliferation in lab studies but tends to have the opposite effect in clinical practice, where tumor cells adapt to them and often become resistant to treatment with radiation, chemotherapy, and immune checkpoint blockade. Interferons are produced in the immune and other cells, including some types of cancer cells.

“We determined that a subset of PDAC tumors exhibit an intrinsic interferon response that has not been modeled by standard cell culture conditions. Using several advanced techniques, we found that interferon signaling causes the tumor cells to rely on a specific signaling pathway for survival,” said Evan R. Abt, a postdoctoral researcher in Radu’s lab and co-first author of the article with Thuc M Le, adjunct assistant professor in Molecular and Medical Pharmacology, and Amanda M. Dann, MD, a resident in surgery at the UCLA David Geffen School of Medicine.

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“However,” Abt added, “if we inhibit a protein called ATR, which plays an important role in this signaling pathway, we can cause catastrophic damage to the cancer cells’ DNA and induce programmed cell death.”

Timothy Donahue, MD, a pancreas cancer surgeon and an expert in pancreas cancer biology. Donahue is the Chief of the Division of Surgical Oncology and Professor of Surgery at the David Geffen School of Medicine at UCLA. He also has a joint appointment in the Department of Molecular and Medical Pharmacology to facilitate his research program. Dr. Donahue is the Surgical Director of the UCLA Agi Hirshberg Center for Pancreatic Diseases.

No escape
Results suggest that new small molecule drugs that inhibit ATR and are being studied for the treatment of several cancers, including PDAC, could be used in combination with interferon “amplification” to thwart the tumor cells’ ability to escape.

The researchers defined a series of molecular interactions leading to a cascade of intracellular events. Through its influence on several genes, interferon alters the metabolic processes supporting the foundation of the cancer cells’ DNA, reducing the supply of biochemical building blocks needed for the DNA to survive. To compensate, the cancer cells rely on a signaling pathway – the replication stress response signaling pathway – that can enable threatened DNA to survive, largely through the influence of ATR.

Donahue explained that one potential intervention deserving further exploration, according to the results of the study, therapy that activates another signaling pathway, called Stimulator of Interferon Genes or STING.

“STING activation induces interferon signaling in PDAC cells and triggers ATR activation,” he said. “This strategy would enhance the attack brought about through interferon signaling while preventing escape through the collateral pathway by shutting it down with ATR-inhibiting drugs.”

Other studies
In an unrelated study, published in the September 7, 2021 edition of Proceedings of the National Academy of Sciences (PNAS), the researchers found that IFN signaling augments PDAC cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase or TYMP, which catalyzes the first step in the catabolism of thymidine, and competitively inhibits the intratumoral accumulation of the nucleoside analog PET probe 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT).

Accordingly, treatment with IFN up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression.

In an in vivo study, the investigators observed that genetic activation of STING enhanced the [18F]FLT avidity of xenograft tumors. They also noted that small-molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment.

Based on these findings, the investigators believe that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

[1] Abt ER, Le TM, Dann AM, Capri JR, Poddar S, Lok V, Li L, Liang K, Creech AL, Rashid K, Kim W, Wu N, Cui J, Cho A, Lee HR, Rosser EW, Link JM, Czernin J, Wu TT, Damoiseaux R, Dawson DW, Donahue TR, Radu CG. Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells. Cell Rep. 2022 Jan 11;38(2):110236. doi: 10.1016/j.celrep.2021.110236. PMID: 35021095.
[2] Liang K, Abt ER, Le TM, Cho A, Dann AM, Cui J, Li L, Rashid K, Creech AL, Wei L, Ghukasyan R, Rosser EW, Wu N, Carlucci G, Czernin J, Donahue TR, Radu CG. STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging. Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2105390118. doi: 10.1073/pnas.2105390118. PMID: 34480004; PMCID: PMC8433573.

Featured image.  Pancreas. Photo courtesy: © 2016 – 2022 UCLA Jonsson Comprehensive Cancer Center/Fotolia/Adobe. Used with permission.

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