Improving PET Evaluation of Brain Tumors

To survive and proliferate, cancer cells undergo metabolic reprogramming and avidly consume various nutrients, including glucose. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), a glucose analog, is usually the radiolabeled tracer of choice when PET is used to evaluate tumors.

However, not all cancers can be clearly imaged with ¹⁸F-FDG–based PET, including glioma, an aggressive form of brain cancer. “It's difficult to distinguish these tumors, because normal brain cells also metabolize high amounts of glucose,” says Sriram Venneti, MD, PhD, a neuropathologist at the University of Michigan in Ann Arbor and first author of a recent study showing that ¹⁸F-fluoroglutamine (¹⁸F-FGln), an analog of the amino acid glutamine, is a more specific PET tracer for glioma in mice and humans (Sci Transl Med 2015;7:274ra17).

Highly dependent on glutamine, many cancers synthesize it and import still more from extracellular sources. Hypothesizing that “this addiction could be leveraged to noninvasively assess brain tumors,” Venneti collaborated with colleagues at Memorial Sloan Kettering Cancer Center in New York, NY, and the University of Pennsylvania in Philadelphia to develop ¹⁸F-FGln.

In several mouse models of glioma, the researchers found that the uptake of ¹⁸F-FGln was significantly higher in tumors than in normal brain tissue. In contrast, the uptake of ¹⁸F-FDG was equivalent in tumors and normal tissue. With ¹⁸F-FGln, tumor-to-background ratios ranged from 4:1 to 6:1, enabling clear tumor delineation; this ratio was approximately 1:1 with ¹⁸F-FDG. The researchers verified that the marked ¹⁸F-FGln uptake seen in glioma was not influenced by neuroinflammation or a leaky blood–brain barrier.

Venneti's team then compared ¹⁸F-FGln with MRI in imaging glioma-bearing mice before and after treatment with chemotherapy and radiation. ¹⁸F-FGln's uptake dropped significantly after treatment; however, MRI scans before and after were not appreciably different.

Ralph DeBerardinis, MD, PhD, an associate professor at the University of Texas Southwestern Medical Center in Dallas, is encouraged that ¹⁸F-FGln–based PET “reports therapy-induced metabolic changes in these mice long before tumor size changes” on MRI. “This is exactly what glucose-based PET monitors in many other cancers, but has been difficult to capture in gliomas,” he says.

Additionally, ¹⁸F-FGln–based PET may help separate pseudoprogression—a treatment-related MRI pattern mimicking disease progression—from actual tumor recurrence, “a difficult distinction to make in the clinic,” Venneti adds.

Testing the agent in patients who had undergone surgery, Venneti and his colleagues saw avid uptake and retention of ¹⁸F-FGln in three patients whose gliomas recurred, but not in three others whose tumors had not. Where ¹⁸F-FDG outlined only part of the tumor in one patient, ¹⁸F-FGln clearly delineated the same tumor in its entirety—which is important, Venneti notes, because gliomas are highly invasive.

“Hopefully, this agent performs as well outside the brain,” says Peter Choyke, MD, director of the NCI's molecular imaging program in Bethesda, MD. “It will be particularly interesting to see whether glutamine uptake in tumors leads to clinical responses for a new generation of drugs targeting glutamine transport and metabolism.”

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