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

Rimas V. Lukas*, Csaba Juhász, Derek A. Wainwright, Charles David James, Eugene Kennedy, Roger Stupp, Maciej S. Lesniak

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

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-[ 11 C]-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.

Original languageEnglish (US)
Pages (from-to)111-120
Number of pages10
JournalJournal of Neuro-Oncology
Volume141
Issue number1
DOIs
StatePublished - Jan 15 2019

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Glioblastoma
Tryptophan
Positron-Emission Tomography
temozolomide
Kynurenine
Central Nervous System Neoplasms
Neoplasms
Adjuvant Radiotherapy
Essential Amino Acids
Enzyme Inhibitors
Therapeutics
Clinical Protocols
1-methyltryptophan
Glioma
Immunosuppression
Drug Therapy
Survival
Brain
Enzymes

Keywords

  • 1-MT
  • AMT
  • Biomarker
  • Glioblastoma
  • IDO
  • Indoximod
  • PET

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

@article{1cc728121be148dbb56f943f0d568acf,
title = "Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod",
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-[ 11 C]-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.",
keywords = "1-MT, AMT, Biomarker, Glioblastoma, IDO, Indoximod, PET",
author = "Lukas, {Rimas V.} and Csaba Juh{\'a}sz and Wainwright, {Derek A.} and James, {Charles David} and Eugene Kennedy and Roger Stupp and Lesniak, {Maciej S.}",
year = "2019",
month = "1",
day = "15",
doi = "10.1007/s11060-018-03013-x",
language = "English (US)",
volume = "141",
pages = "111--120",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",
number = "1",

}

TY - JOUR

T1 - Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod

AU - Lukas, Rimas V.

AU - Juhász, Csaba

AU - Wainwright, Derek A.

AU - James, Charles David

AU - Kennedy, Eugene

AU - Stupp, Roger

AU - Lesniak, Maciej S.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - 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-[ 11 C]-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.

AB - 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-[ 11 C]-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.

KW - 1-MT

KW - AMT

KW - Biomarker

KW - Glioblastoma

KW - IDO

KW - Indoximod

KW - PET

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U2 - 10.1007/s11060-018-03013-x

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VL - 141

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EP - 120

JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

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