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

Background: 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. Materials and Methods: Three positron emission tomography (PET) clinical imaging agents, [ ¹⁸ F]fluoro-2-deoxy-2-D-glucose ([ ¹⁸ F]FDG), 3'-[ ¹⁸ F]fluoro-3'-deoxythymidine ([ ¹⁸ F]FLT), and (2S, 4R)-4-[ ¹⁸ F]fluoroglutamine ([ ¹⁸ F]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. Results: Drug treatment altered tumor uptake of all three PET agents. Relative [ ¹⁸ F]FDG uptake decreased significantly after telaglenastat treatment, but not within control and metformin-only groups. [ ¹⁸ F]FLT tumor uptake appears to be negatively affected by tumor size. Evidence of a flare effect was seen with [ ¹⁸ F]FLT imaging after treatment. Telaglenastat had a broad influence on [ ¹⁸ F]GLN uptake in tumor and normal tissues. Conclusions: Image-based tumor volume quantification is recommended for this paratibial tumor model. The performance of [ ¹⁸ F]FLT and [ ¹⁸ F]GLN was affected by tumor size. [ ¹⁸ F]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 [ ¹⁸ F]GLN uptake in patients receiving telaglenastat.