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Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids

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Abstract

Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2–4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1WT gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development.

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Abbreviations

AA:

Anaplastic astrocytoma

AG:

Anaplastic glioma

AMG:

Anaplastic mixed glioma

AO:

Anaplastic oligodendroglioma

ASN:

Asparagine

ASNS:

Asparagine synthetase

BCAA:

Branched chain amino acids

BCAT:

Branched chain amino-acid aminotransferase

GBM:

Glioblastoma multiforme

GLN:

Glutamine

GLS:

Glutaminase

IDH:

Isocitrate dehydrogenase

IDH1WT :

Isocitrate dehydrogenase 1, wild type

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Authors and Affiliations

  1. Harbor-UCLA Medical Center/Los Angeles Biomedical Research Institute (LA BioMed), 1000 W. Carson Street, N25, Box 468, Torrance, CA, 90509, USA

    Eduard H. Panosyan, Joseph L. Lasky, Henry J. Lin, Yang Hai & Xiuqing Guo

  2. UCLA Neuro-Oncology, 710 Westwood Plaza, Reed Bldg RM 1-230, Los Angeles, CA, 90095, USA

    Albert Lai, Timothy F. Cloughesy & P. Leia Nghiemphu

  3. SiliconMED North America Inc., 445 Park Avenue, 9th Floor, New York, NY, 10022, USA

    Michael Quinn

  4. Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA

    Stanley F. Nelson

Authors
  1. Eduard H. Panosyan
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  2. Joseph L. Lasky
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  3. Henry J. Lin
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  4. Albert Lai
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  8. Stanley F. Nelson
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  9. Timothy F. Cloughesy
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  10. P. Leia Nghiemphu
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Corresponding author

Correspondence to Eduard H. Panosyan.

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Conflict of Interest

Eduard H. Panosyan: Consultation and compensation from: Baxter, Octapharma, CSL Behring, Jazz Pharmaceuticals. Joseph L. Lasky: Consultation and compensation from: Baxter, Octapharma, CSL Behring. Henry J. Lin: None. Albert Lai: Consultancy with Genentech/Roche, research funding from Takeda/Millennium and Genentech/Roche. Yang Hai: None. Xiuqing Guo: None. Michael Quinn: Contracts with the following academic medical centers: Ronald Reagan UCLA Medical Center, Keck School of Medicine of University of Southern California and Kaiser Permanente. No industry sponsored contracts. Stanley F. Nelson: None. Timothy F. Cloughesy: Consultant with and compensation from: Roche, Genentech, Upshire Smith, VBL, Abbvie, Nektar, Novocure, Tocagen, Notable labs, Novartis, Celgene, Lpath, Proximagen, Amgen, Newgen. Expert testimony: Roche. Phioanh L. Nghiemphu: None.

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Panosyan, E.H., Lasky, J.L., Lin, H.J. et al. Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids. J Neurooncol 128, 57–66 (2016). https://doi.org/10.1007/s11060-016-2073-5

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  • DOI: https://doi.org/10.1007/s11060-016-2073-5

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