A new study from scientists at the UCLA Jonsson Comprehensive Cancer Center found that emerging drugs that activate the protein STING, a well-established regulator of immune cell activation, substantially alter the activity of metabolic pathways responsible for generating the nucleotide building blocks for DNA.
Researchers found that these alterations occur in cancer cells and can be visualized using [18F]FLT positron emission tomography (PET) imaging, marking the first time the effects of these drugs have been traced using a noninvasive imaging technique. Understanding how STING agonists impact metabolic processes can help accelerate the clinical development of STING activating drugs in various therapeutic settings and guide the design of novel biomarkers and combination therapies. The team published its study, “STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging,” in PNAS.
“Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling–induced alterations in tumor cell metabolism can be detected using PET has not been investigated,” the investigators wrote.
“We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT).
“Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling–dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment.
“These findings indicate 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.”
The study provides evidence that STING activating drugs have potent effects on the activity of metabolic pathways in pancreas cancer cells, according to the researchers. The observation that STING activation can be monitored noninvasively using [18F]FLT PET provides researchers and physicians with a new tool to track the duration and localization of the effects of STING agonists.
This information could be used to fine-tune and customize treatments to help more people with hard-to-treat cancers and other diseases where STING activation may be beneficial.