BIMG-13. A NOVEL RADIOPHARMACEUTICAL ([(18)F]DASA-23) TO MONITOR PYRUVATE KINASE M2 INDUCED GLYCOLYTIC REPROGRAMMING IN GLIOBLASTOMA

BACKGROUND: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) cells with minimal expression in healthy brain, making it an important biomarker of cancer glycolytic re-programming. We describe the bench-to-bedside development, validation, and translation of a novel positron emission tomography (PET) tracer to study PKM2 in GBM. Specifically, we evaluated 1-((2-fluoro-6-[(18)F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([(18)F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and GBM patients. METHODS: [(18)F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/µmol and radiochemical purity >95%. We performed initial testing of [(18)F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next we produced [(18)F]DASA-23 under current Good Manufacturing Practices United States Food and Drug Administration (FDA) oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with gliomas. RESULTS: In mouse imaging studies, [(18)F]DASA-23 clearly delineated the U87 GBM from the surrounding healthy brain tissue and had a tumor-to-brain ratio (TBR) of 3.6 ± 0.5. In human volunteers, [(18)F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In GBM patients, [(18)F]DASA-23 successfully outlined tumors visible on contrast-enhanced magnetic resonance imaging (MRI). The uptake of [(18)F]DASA-23 was markedly elevated in GBMs compared to normal brain, and it was able to identify a metabolic non-responder within 1-week of treatment initiation. CONCLUSION: We developed and translated [(18)F]DASA-23 as a promising new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These encouraging results warrant further clinical evaluation of [(18)F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.