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Mol Imaging Biol. 2019 Apr 15. doi: 10.1007/s11307-019-01353-2. [Epub ahead of print]

Evaluation of Glycolytic Response to Multiple Classes of Anti-glioblastoma Drugs by Noninvasive Measurement of Pyruvate Kinase M2 Using [18F]DASA-23.

Author information

1
Molecular Imaging Program at Stanford, Department of Radiology, James H. Clark Center, Stanford University School of Medicine, 318 Campus Drive, E153, Stanford, CA, 94305, USA.
2
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
3
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410002, Hunan, China.
4
Molecular Imaging Program at Stanford, Department of Radiology, James H. Clark Center, Stanford University School of Medicine, 318 Campus Drive, E153, Stanford, CA, 94305, USA. sgambhir@stanford.edu.
5
Department of Bioengineering and Materials Science and Engineering, Bio-X, Stanford University, Stanford, CA, 94305, USA. sgambhir@stanford.edu.

Abstract

PURPOSE:

Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, the key process of tumor metabolism. PKM2 is found in high levels in glioblastoma (GBM) cells with marginal expression within healthy brain tissue, rendering it a key biomarker of GBM metabolic re-programming. Our group has reported the development of a novel radiotracer, 1-((2-fluoro- 6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA- 23), to non-invasively detect PKM2 levels with positron emission tomography (PET).

PROCEDURE:

U87 human GBM cells were treated with the IC50 concentration of various agents used in the treatment of GBM, including alkylating agents (temozolomide, carmustine, lomustine, procarbazine), inhibitor of topoisomerase I (irinotecan), vascular endothelial and epidermal growth factor receptor inhibitors (cediranib and erlotinib, respectively) anti-metabolite (5-fluorouracil), microtubule inhibitor (vincristine), and metabolic agents (dichloroacetate and IDH1 inhibitor ivosidenib). Following drug exposure for three or 6 days (n = 6 replicates per condition), the radiotracer uptake of [18F]DASA-23 and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was assessed. Changes in PKM2 protein levels were determined via Western blot and correlated to radiotracer uptake.

RESULTS:

Significant interactions were found between the treatment agent (n = 12 conditions total comprised 11 drugs and vehicle) and the duration of treatment (3- or 6-day exposure to each drug) on the cellular uptake of [18F]DASA-23 (p = 0.0001). The greatest change in the cellular uptake of [18F]DASA-23 was found after exposure to alkylating agents (p < 0. 0001) followed by irinotecan (p = 0. 0012), erlotinib (p = 0. 02), and 5-fluorouracil (p = 0. 005). Correlation of PKM2 protein levels and [18F]DASA-23 cellular uptake revealed a moderate correlation (r = 0.44, p = 0.15).

CONCLUSIONS:

These proof of principle studies emphasize the superiority of [18F]DASA-23 to [18F]FDG in detecting the glycolytic response of GBM to multiple classes of anti-neoplastic drugs in cell culture. A clinical trial evaluating the diagnostic utility of [18F]DASA-23 PET in GBM patients (NCT03539731) is ongoing.

KEYWORDS:

Glioblastoma; Glycolysis; Pyruvate kinase M2; [18F]DASA-23; [18F]FDG

PMID:
30989436
DOI:
10.1007/s11307-019-01353-2

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