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

  • Corinne Beinat
  • Chirag B. Patel
  • Yuanyang Xie
  • Sanjiv S. GambhirEmail author
Research Article
  • 47 Downloads

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.

Key words

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

Notes

Acknowledgments

We thank the Radiochemistry Facility at Stanford University for the 18F production, in particular Drs. Bin Shen, Jun Hyung Park and Jessa B. Castillo, and Mr. George Montoya for the [18F]FDG production.

Compliance with Ethical Standards

Conflict of Interest

The authors received funding from the following sources: Ben and Catherine Ivy Foundation (Gambhir), American Brain Tumor Association Basic Research Fellowship supported by the Ryan J. Hanrahan Memorial (Patel), Stanford Cancer Institute Fellowship for Cancer Research (Patel), Stanford-Asia Medical Fund C.J. Huang Medical Fellowship (Xie), Stanford School of Medicine Translational Research and Applied Medicine Fellowship (Beinat). The authors report no conflicts of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

11307_2019_1353_MOESM1_ESM.pdf (1.1 mb)
ESM 1 (PDF 1080 kb)

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Copyright information

© World Molecular Imaging Society 2019

Authors and Affiliations

  1. 1.Molecular Imaging Program at Stanford, Department of Radiology, James H. Clark CenterStanford University School of MedicineStanfordUSA
  2. 2.Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA
  3. 3.Department of NeurosurgeryXiangya Hospital, Central South UniversityChangshaChina
  4. 4.Department of Bioengineering and Materials Science and EngineeringBio-X, Stanford UniversityStanfordUSA

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