Imaging Telomerase as a Marker of Response to Therapy

Take-Away Points

• ■ Major Focus: Developing a novel deuterium MRI method to detect telomerase reverse transcriptase (TERT) in cancer.

• ■ Key Results: Reactivation of TERT in cancer cells increases the metabolism of pyruvate to lactate in glycolysis, which the authors detected in preclinical models with deuterium MRI spectroscopy following administration of deuterium-labeled pyruvate.

• ■ Impact: Deuterium MRI for the metabolism of pyruvate to lactate represents a clinically translatable method to detect TERT as a marker of proliferation and response to therapy in cancer.

Malignant cells commonly reactivate TERT, the active component of the telomerase enzyme complex, as a hallmark feature of cancer. TERT prevents the shortening of the ends of chromosomes during cell division, allowing the unlimited proliferation of cancer cells. The central function of TERT in cancer makes the enzyme an appealing drug target in cancer. Developing imaging methods for TERT promises to improve the detection of cancer and early monitoring of treatment efficacy.

Using cell-based and mouse models of glioblastoma and other cancers, Batsios et al discovered that reactivation of TERT in cancer cells led to increased amounts of the metabolic cofactor nicotinamide adenine dinucleotide (NADH). NADH is essential for the metabolism of pyruvate to lactate in glycolysis by the lactate dehydrogenase A enzyme. To indirectly image the expression of TERT, the authors used MRI spectroscopy to quantify the conversion of pyruvate labeled with deuterium, a nonradioactive isotope of hydrogen, to lactate. Deuterium MRI spectroscopy is a clinically translatable imaging method that does not require the expensive instrumentation needed for hyperpolarized MRI of pyruvate. Deuterium MRI detected changes in TERT expression on the basis of the conversion of pyruvate to lactate in a mouse model of cancer. Imaging also detected response to TERT-targeted therapy and standard of care chemotherapy prior to changes in tumor size in patient-derived glioblastoma cells. Importantly, the authors detected changes in deuterium MRI spectroscopy for pyruvate using a 3-T magnet.

This study establishes a new imaging method to detect TERT in living models, setting the stage for initial clinical studies to translate this MRI technique from preclinical models to patients.

Highlighted Article

• Batsios G, Taglang C, Tran M, et al. Deuterium metabolic imaging reports on TERT expression and early response to therapy in cancer [published online ahead of print, July 6, 2022]. Clin Cancer Res 2022;clincanres.CCR-21-4418-A.2021. doi: https://doi.org/10.1158/1078-0432.CCR-21-4418