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Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod

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Abstract

Introduction

Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the central nervous system, accounting for over 50% of all primary malignant gliomas arising in the adult brain. Even after surgical resection, adjuvant radiotherapy (RT) and temozolomide (TMZ) chemotherapy, as well as tumor-treating fields, the median survival is only 15–20 months. We have identified a pathogenic mechanism that contributes to the tumor-induced immunosuppression in the form of increased indoleamine 2,3 dioxygenase 1 (IDO1) expression; an enzyme that metabolizes the essential amino acid, tryptophan (Trp), into kynurenine (Kyn). However, real-time measurements of IDO1 activity has yet to become mainstream in clinical protocols for assessing IDO1 activity in GBM patients.

Methods

Pre-treatment and on-treatment α-[11C]-methyl-l-Trp (AMT) positron emission tomography (PET) with co-registered MRI was performed on patients with recurrent GBM treated with the IDO1 pathway inhibitor indoximod (D1-MT) and TMZ.

Results

Regional intratumoral variability of AMT within enhancing and non-enhancing tumor was noted at baseline. On treatment imaging revealed decreased regional uptake suggesting IDO1 pathway modulation with treatment.

Conclusions

Here, we have validated the ability to use PET of the Trp probe, AMT, for use in visualizing and quantifying intratumoral Trp uptake in GBM patients treated with an IDO1 pathway inhibitor. These data serve as rationale to utilize AMT-PET imaging in the future evaluation of GBM patients treated with IDO1 enzyme inhibitors.

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Funding

M.S. Lesniak is supported by PHS Grant Numbers R01NS093903 awarded by the NIH/NINDS, and P50CA221747 awarded by the NIH/NCI, U.S. Department of Health and Human Services. R.V. Lukas is supported by PHS Grant Number R01NS093903 awarded by the NIH/NINDS and P50CA221747 awarded by the NIH/NCI, U.S. Department of Health and Human Services. D.A. Wainwright is supported by PHS Grant Number R01NS097851 awarded by the NIH/NINDS and P50CA221747 awarded by the NIH/NCI, U.S. Department of Health and Human Services. C. Juhasz is supported by PHS Grant Number R01NS093903 awarded by the NIH/NINDS, and R01CA123451 and P50CA221747 awarded by the NCI/NIH, U.S. Department of Health and Human Services. C.D. James is supported by PHS Grant Number P50CA221747 awarded by the NCI/NIH, U.S. Department of Health and Human Services. R. Stupp is supported by PHS Grant Number P50CA221747 awarded by the NIH/NCI, U.S. Department of Health and Human Services.

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Authors and Affiliations

  1. Department of Neurology, Northwestern University, 710 N. Lake Shore Drive, Abbott Hall 1114, Chicago, IL, 60611, USA

    Rimas V. Lukas & Roger Stupp

  2. Department of Neurosurgery, Northwestern University, Chicago, USA

    Derek A. Wainwright, Charles David James, Roger Stupp & Maciej S. Lesniak

  3. Lurie Cancer Center, Northwestern University, Chicago, USA

    Rimas V. Lukas, Derek A. Wainwright, Charles David James, Roger Stupp & Maciej S. Lesniak

  4. Lou & Jean Malnati Brain Tumor Institute, Northwestern University, Chicago, USA

    Rimas V. Lukas, Derek A. Wainwright, Charles David James, Roger Stupp & Maciej S. Lesniak

  5. Neurology, and Neurosurgery, Department of Pediatrics, Wayne State University, Detroit, USA

    Csaba Juhász

  6. Karmanos Cancer Institute, Wayne State University, Detroit, USA

    Csaba Juhász

  7. NewLink Genetics, Ames, USA

    Eugene Kennedy

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  1. Rimas V. Lukas
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  2. Csaba Juhász
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  3. Derek A. Wainwright
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  4. Charles David James
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  5. Eugene Kennedy
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  6. Roger Stupp
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  7. Maciej S. Lesniak
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Correspondence to Rimas V. Lukas.

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Conflict of interest

E. Kennedy is an employee of New Link Genetics. All other authors report no conflicts of interest.

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This research was conducted in compliance with the ethical standards of the institutional research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Lukas, R.V., Juhász, C., Wainwright, D.A. et al. Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod. J Neurooncol 141, 111–120 (2019). https://doi.org/10.1007/s11060-018-03013-x

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  • DOI: https://doi.org/10.1007/s11060-018-03013-x

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