A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2–Induced Glycolytic Reprogramming in Glioblastoma

• Published in: Clinical cancer research Vol. 27; no. 23; pp. 6467 - 6478
• Main Authors: Beinat, Corinne, Patel, Chirag B., Haywood, Tom, Murty, Surya, Naya, Lewis, Castillo, Jessa B., Reyes, Samantha T., Phillips, Megan, Buccino, Pablo, Shen, Bin, Park, Jun Hyung, Koran, Mary Ellen I., Alam, Israt S., James, Michelle L., Holley, Dawn, Halbert, Kim, Gandhi, Harsh, He, Joy Q., Granucci, Monica, Johnson, Eli, Liu, Daniel Dan, Uchida, Nobuko, Sinha, Rahul, Chu, Pauline, Born, Donald E., Warnock, Geoffrey I., Weissman, Irving, Hayden-Gephart, Melanie, Khalighi, Mehdi, Massoud, Tarik F., Iagaru, Andrei, Davidzon, Guido, Thomas, Reena, Nagpal, Seema, Recht, Lawrence D., Gambhir, Sanjiv Sam
• Format: Journal Article
• Language: English
• Published: United States 01.12.2021
• Subjects: Animals; Brain Neoplasms - pathology; Diazonium Compounds; Glioblastoma - pathology; Glycolysis; Humans; Mice; Positron-Emission Tomography - methods; Pyruvate Kinase - metabolism; Sulfanilic Acids
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-21-0544

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. We describe the development, validation, and translation of a novel PET tracer to study PKM2 in GBM. We evaluated 1-((2-fluoro-6-[ F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([ F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. [ 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 [ F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [ F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. In mouse imaging studies, [ F]DASA-23 clearly delineated the U87 GBM from surrounding healthy brain tissue and had a tumor-to-brain ratio of 3.6 ± 0.5. In human volunteers, [ F]DASA-23 crossed the intact blood-brain barrier and was rapidly cleared. In patients with GBM, [ F]DASA-23 successfully outlined tumors visible on contrast-enhanced MRI. The uptake of [ F]DASA-23 was markedly elevated in GBMs compared with normal brain, and it identified a metabolic nonresponder within 1 week of treatment initiation. We developed and translated [ F]DASA-23 as a new tracer that demonstrated the visualization of aberrantly expressed PKM2 for the first time in human subjects. These results warrant further clinical evaluation of [ F]DASA-23 to assess its utility for imaging therapy-induced normalization of aberrant cancer metabolism.