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Role of Kynurenine Pathway in Neuro-oncology

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Targeting the Broadly Pathogenic Kynurenine Pathway

Abstract

Despite decades of research, both primary and metastatic brain tumors remain intractable clinical problems. While the kynurenine (KYN) pathway of tryptophan metabolism has been well explored in other cancer types, there are few studies of human brain tumors. The rate-limiting enzymes of the conversion of tryptophan to kynurenine (both forms of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2)) have been studied predominantly in gliomas with in vitro methods, in vivo animal studies, and ex vivo tissue studies of surgically resected specimens. In these studies, IDO1 has been shown regulated by interferon-γ (as in other cancer types) and TDO2 by the glucocorticoid receptor. IDO and TDO2 have also been positively correlated with tumor grade and negatively correlated with patient survival in glioma. One seminal study also identified KYN as an activator of the aryl hydrocarbon receptor (not previously shown in any other cancer types). Therefore, the KYN pathway may represent new opportunities for treatment strategies for brain tumors.

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Abbreviations

3-HK:

3-Hydroxykynurenine

AMT:

α-[11C]-methyl-L-tryptophan

TCDD:

2,3,7,8-Tetrachlorodibenzo-p-dioxin

AhR:

Aryl hydrocarbon receptor

CNS:

Central nervous system

FKBP52:

FK506-binding protein 52kDa

GBM:

Glioblastoma

GR:

Glucocorticoid receptor

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon-γ

KYNA:

Kynurenic acid

KYN:

Kynurenine

KMO:

Kynurenine 3-monooxygenase

MRI:

Magnetic resonance imaging

MEN:

Meningioma

MBT:

Metastatic brain tumor

PET:

Positron emission tomography

QUIN:

Quinolinic acid

Tregs:

Regulatory T cells

TRP:

Tryptophan

TDO2:

Tryptophan 2,3-dioxygenase

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Acknowledgments

This work is supported by NIH/NCI R01 grant CA123451 (SM) and Strategic Research Support from the Karmanos Cancer Institute (SM).

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Authors and Affiliations

  1. Department of Neurosurgery, Wayne State University, 4160 John R Street, Suite 930, Detroit, MI, 48201, USA

    Sharon K. Michelhaugh, Kaushik Varadarajan & Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.

  2. Department of Oncology, Wayne State University School of Medicine, 4160 John R St, Suite 930, Detroit, 48201, MI, USA

    Anthony R. Guastella & Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.

  3. Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

    Anthony R. Guastella

  4. Karmanos Cancer Institute, Detroit, MI, USA

    Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.

Authors
  1. Sharon K. Michelhaugh
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  2. Kaushik Varadarajan
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  3. Anthony R. Guastella
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  4. Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S.
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Corresponding author

Correspondence to Sandeep Mittal M.D., F.R.C.S.C., F.A.C.S. .

Editor information

Editors and Affiliations

  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

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Michelhaugh, S.K., Varadarajan, K., Guastella, A.R., Mittal, S. (2015). Role of Kynurenine Pathway in Neuro-oncology. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_22

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