Exploration of Imaging Biomarkers for Metabolically-Targeted Osteosarcoma Therapy in a Murine Xenograft Model

Osteosarcoma (OS) is an aggressive pediatric cancer with unmet therapeutic needs. Glutaminase 1 (GLS1) inhibition, alone and in combination with metformin, disrupts the bioenergetic demands of tumor progression and metastasis, showing promise for clinical translation. Three positron emission tomography (PET) clinical imaging agents, [¹⁸F]fluoro-2-deoxy-2-D-glucose ([¹⁸F]FDG), 3'-[¹⁸F]fluoro-3'-deoxythymidine ([¹⁸F]FLT), and (2S, 4R)-4-[¹⁸F]fluoroglutamine ([¹⁸F]GLN), were evaluated in the MG63.3 human OS xenograft mouse model, as companion imaging biomarkers after treatment for 7 d with a selective GLS1 inhibitor (CB-839, telaglenastat) and metformin, alone and in combination. Imaging and biodistribution data were collected from tumors and reference tissues before and after treatment. Drug treatment altered tumor uptake of all three PET agents. Relative [¹⁸F]FDG uptake decreased significantly after telaglenastat treatment, but not within control and metformin-only groups. [¹⁸F]FLT tumor uptake appears to be negatively affected by tumor size. Evidence of a flare effect was seen with [¹⁸F]FLT imaging after treatment. Telaglenastat had a broad influence on [¹⁸F]GLN uptake in tumor and normal tissues. Image-based tumor volume quantification is recommended for this paratibial tumor model. The performance of [¹⁸F]FLT and [¹⁸F]GLN was affected by tumor size. [¹⁸F]FDG may be useful in detecting telaglenastat's impact on glycolysis. Exploration of kinetic tracer uptake protocols is needed to define clinically relevant patterns of [¹⁸F]GLN uptake in patients receiving telaglenastat.