PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2
Menée à l'aide de modèles murins, cette étude évalue les performances d'une technique d'imagerie qui, en mesurant des anomalies de glycolyse, permet de détecter des tumeurs de glioblastome multiforme
Tumor cells are well known to have metabolic abnormalities that are not present in normal cells, and positron emission tomography (PET) imaging relies on these abnormalities to identify tumors within a patient’s body. Unfortunately, the most common type of PET imaging is based on detection of cells that most actively use glucose, and thus, it cannot detect tumors in the brain, where even the normal cells require large amounts of glucose. Now, Witney et al. have developed a new PET imaging reagent, which detects abnormalities of glycolysis that are specifically associated with brain tumors but not normal brain, allowing a clear differentiation of the two in mouse models.
Cancer cells reprogram their metabolism to meet increased biosynthetic demands, commensurate with elevated rates of replication. Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in tumor glycolysis, controlling the balance between energy production and the synthesis of metabolic precursors. We report here the synthesis and evaluation of a positron emission tomography (PET) radiotracer, [11C]DASA-23, that provides a direct noninvasive measure of PKM2 expression in preclinical models of glioblastoma multiforme (GBM). In vivo, orthotopic U87 and GBM39 patient-derived tumors were clearly delineated from the surrounding normal brain tissue by PET imaging, corresponding to exclusive tumor-associated PKM2 expression. In addition, systemic treatment of mice with the PKM2 activator TEPP-46 resulted in complete abrogation of the PET signal in intracranial GBM39 tumors. Together, these data provide the basis for the clinical evaluation of imaging agents that target this important gatekeeper of tumor glycolysis.
Science Translational Medicine , résumé, 2014