Supplementary Table S5 from A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate Kinase M2–Induced Glycolytic Reprogramming in Glioblastoma (original) (raw)
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Clinical Cancer Research, 2021
Purpose: 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-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) in cell culture, mouse models of GBM, healthy human volunteers, and patients with GBM. Experimental Design: [18F]DASA-23 was synthesized with a molar activity of 100.47 ± 29.58 GBq/μmol and radiochemical purity >95%. We performed initial testing of [18F]DASA-23 in GBM cell culture and human GBM xenografts implanted orthotopically into mice. Next, we produced [18F]DASA-23 under FDA oversight, and evaluated it in healthy volunteers and a pilot cohort of patients with glioma. Results: In mouse imaging studies, [18F]DASA-23 clearly delineated the U87 GBM from surrou...
Science translational medicine, 2015
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, [(11)C]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 i...
Metabolic and hemodynamic evaluation of gliomas using positron emission tomography
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1987
Positron emission tomography (PET) was used on 16 patients with untreated cerebral gliomas to measure cerebral glucose and oxygen metabolism, oxygen extraction, blood flow, and blood volume. In addition, pH values were obtained for seven cases. Gliomas were later proven by biopsy; two patients had tumors with degrees of malignancy of grade II, two patients had grade III, and 12 patients had grade IV tumors. Compared with homologous gray matter regions in the opposite hemisphere, tumor tissue showed increased blood volume, but decreased oxygen extraction and oxygen metabolism. Compared with grade II tumors, grade IV tumors demonstrated higher blood volumes, but lower relative oxygen extraction and utilization. Tumor blood flow was variable, but was lower in the higher grade tumors. Rates of glucose utilization in tumor, calculated by using individually determined rate constants, were variable, and did not correlate with tumor size or tumor grade. Parietal tumors (n = 6) tended to hav...
Journal of Neuro-Oncology, 2009
Purpose To monitor the metabolic effects of an individual patient-tailored, experimental glioma therapy regimen that included repetitive multiple neurosurgical resections, radiosurgical interventions, and an adjuvant maintenance therapy based on the tyrosine kinase inhibitor imatinib in combination with the chemotherapeutic agent hydroxyurea (HU). Procedures Therapeutic effects were monitored in a 26-year-old male patient with a glioblastoma multiforme by multimodal imaging using sequential L-[methyl-(11)C]-methionine positron emission tomography (MET-PET) and MRI. The normalized MET uptake and volume of the metabolically active tumor were assessed sequentially. Results The individual patient-tailored, experimental glioma therapy caused a continuous decline of metabolically active tumor volume, associated with clinical remission over a period of more than two years. Conclusions MET-PET seems to be useful for monitoring patient-tailored, experimental glioma therapy regimens, especially when patients are treated with a multi-step therapeutic regimen. Monitoring and guidance of those experimental therapy regimens by MET-PET in a larger patient group are needed to confirm its clinical value.
Role of PET in the management of gliomas: The radiopharmacist's and clinician's point of view
Médecine Nucléaire, 2015
Positron emission tomography (PET) using fluorodeoxyglucose (FDG), a metabolic imaging modality widely used in systemic cancer, was proposed as a valuable tool for obtaining additional data for diagnosis and better treatment of patients with glioma. Unfortunately physiological uptake of FDG is high in the brain and other radioligands have been developed for neuro-oncology explorations. Based on the point of view of a radiopharmacist and a neuro-oncologist, this review describes the compounds used to explore pathophysiological processes such as proliferation rate, amino acid transport, protein synthesis, hypoxia, and membrane biosynthesis in gliomas and discusses the clinical impact of PET neuroimaging in initial diagnosis, tumour grading, and response to chemotherapy or radiotherapy. Molecular imaging modalities will be compared with magnetic resonance (MR) tools as will be the usefulness of MR/PET multimodality imaging.
2023
Purpose: Structural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma. Experimental Design: Prior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/ flow (CBV/CBF) and vascular permeability (k trans) as well as 18 F-Fluoromisonidazole (18 F-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival. Results: Fifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment 18 F-FMISO SUV peak (P ¼ 0.048), mean k trans (P ¼ 0.024), and median k trans (P ¼ 0.045) were significantly associated with shorter overall survival. Higher pretreatment median k trans (P ¼ 0.021), normalized RCBV (P ¼ 0.0096), and nCBF (P ¼ 0.038) were significantly associated with shorter progression-free survival. SUV peak [AUC ¼ 0.75; 95% confidence interval (CI), 0.59-0.91], nRCBV (AUC ¼ 0.72; 95% CI, 0.56-0.89), and nCBF (AUC ¼ 0.72; 95% CI, 0.56-0.89) were predictive of survival at 1 year. Conclusions: Increased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and 18 F-FMISO PET. Clin Cancer Res; 22(20);
Journal of Neuro-Oncology, 1995
Cerebral hemocirculation and glucose metabolism in a malignant astrocytoma were repeatedly quantified before and after intracarotid injection of recombinant human tumor necrosis factor-a (rH-TNF) using positron emission tomography (PET). The patient received an intracarotid injection of a 3 x 104 U/m 2 dose of rH-TNF three times over a two week period. PET was performed prior to and 24 hr after the first injection, and two weeks after the third injection. Prior to the first rH-TNF treatment, two lesions demonstrating high perfusion and hypermetabolism of glucose were noted in the right frontal and temporal regions. The frontal hypermetabolic lesion showed decreases in hemocirculation and metabolism 24 hr after the first injection and then increases beyond the pre-treatment level two weeks after the third treatment, whereas the temporal lesion remained unchanged during the follow-up period. No appreciable changes were noted in the adjacent cortex where rH-TNF was perfused, with the exception of a transient decrease in regional blood volume. Magnetic resonance images of the tumor showed no changes as a result of treatment with intracarotid rH-TNK Intracarotid rH-TNF preferentially affects tumor tissue as opposed to normal cortex.
Neuro-Oncology Advances, 2021
Background Glioblastoma remains incurable despite treatment with surgery, radiation therapy, and cytotoxic chemotherapy, prompting the search for a metabolic pathway unique to glioblastoma cells.13C MR spectroscopic imaging with hyperpolarized pyruvate can demonstrate alterations in pyruvate metabolism in these tumors. Methods Three patients with diagnostic MRI suggestive of a glioblastoma were scanned at 3 T 1–2 days prior to tumor resection using a 13C/1H dual-frequency RF coil and a 13C/1H-integrated MR protocol, which consists of a series of 1H MR sequences (T2 FLAIR, arterial spin labeling and contrast-enhanced [CE] T1) and 13C spectroscopic imaging with hyperpolarized [1-13C]pyruvate. Dynamic spiral chemical shift imaging was used for 13C data acquisition. Surgical navigation was used to correlate the locations of tissue samples submitted for histology with the changes seen on the diagnostic MR scans and the 13C spectroscopic images. Results Each tumor was histologically confi...