A clinical PET imaging tracer ([18F]DASA-23) to monitor pyruvate kinase M2–induced glycolytic reprogramming in glioblastoma

Abstract

Purpose: Pyruvate kinase M2 (PKM2) catalyzes the final step in Results: In mouse imaging studies, [18F]DASA-23 clearly delinglycolysis, a key process of cancer metabolism. PKM2 is preferentially eated the U87 GBM from surrounding healthy brain tissue and had expressed by glioblastoma (GBM) cells with minimal expression in a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, healthy brain. We describe the development, validation, and transla-[18F]DASA-23 crossed the intact blood–brain barrier and was tion of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-rapidly cleared. In patients with GBM, [18F]DASA-23 successfully fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl) outlined tumors visible on contrast-enhanced MRI. The uptake of piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, [18F]DASA-23 was markedly elevated in GBMs compared with healthy human volunteers, and patients with GBM. normal brain, and it identified a metabolic nonresponder within Experimental Design: [18F]DASA-23 was synthesized with a 1 week of treatment initiation. molar activity of 100.47 ± 29.58 GBq/mmol and radiochemical Conclusions: We developed and translated [18F]DASA-23 as a purity >95%. We performed initial testing of [18F]DASA-23 in GBM new tracer that demonstrated the visualization of aberrantly cell culture and human GBM xenografts implanted orthotopically expressed PKM2 for the first time in human subjects. These results into mice. Next, we produced [18F]DASA-23 under FDA oversight, warrant further clinical evaluation of [18F]DASA-23 to assess its and evaluated it in healthy volunteers and a pilot cohort of patients utility for imaging therapy–induced normalization of aberrant with glioma. cancer metabolism.