RT Journal Article
T1 Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors.
A1 Hajji, Nabil
A1 Garcia-Revilla, Juan
A1 Soto, Manuel Sarmiento
A1 Perryman, Richard
A1 Symington, Jake
A1 Quarles, Chad C
A1 Healey, Deborah R
A1 Guo, Yijie
A1 Orta-Vazquez, Manuel Luis
A1 Mateos-Cordero, Santiago
A1 Shah, Khalid
A1 Bomalaski, John
A1 Anichini, Giulio
A1 Tzakos, Andreas G
A1 Crook, Timothy
A1 O'Neill, Kevin
A1 Scheck, Adrienne C
A1 Venero, Jose Luis
A1 Syed, Nelofer
K1 Amino acid metabolism
K1 Brain cancer
K1 Nitric oxide
K1 Oncology
K1 Therapeutics
AB New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1-positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.
PB American Society for Clinical Investigation
YR 2022
FD 2022-03-15
LK http://hdl.handle.net/10668/20205
UL http://hdl.handle.net/10668/20205
LA en
NO Hajji N, Garcia-Revilla J, Soto MS, Perryman R, Symington J, Quarles CC, et al. Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors. J Clin Invest. 2022 Mar 15;132(6):e142137.
NO This work was supported by the Brain Tumour Research Campaign (BTRC), Brain Tumour Research (BTR) CRUK Convergence Science Centre at The Institute of Cancer Research, London, and Imperial College London (C309/A31316) and the European Regional Development Fund (ERDF) under the Operational Program Epirus 2014-2020, NSRF 2014-2020 (project code 5033092, BIOPREDICTOR) and by the Hellenic Foundation for Research and Innovation (HFRI) under the “First call for HFRI research projects to support faculty members and researchers and the procurement of high-cost research equipment grant” (project code: 991, PROTECT). This research was also funded from grants by the Spanish Ministerio de Ciencia, Innovación y Universidades/FEDER/UE RTI2018-098645-B-100) and from Consejería de Economía y Conocimiento of Junta de Andalucía/FEDER/UE P18-RT-1372 and US-1264806. BTRC and BTR grants were awarded to NS and KON. JS was a recipient of CRUK Clinical Academic Training Programme. ADI-PEG20 was a gift from Polaris Pharmaceuticals Inc. We thank Modesto Carballo, Laura Navarro, and Cristina Reyes (Servicio de Biología, CITIUS, Universidad de Sevilla) for their efficient and friendly help with experiments performed at the facilities. We also thank Aliya Anil from the Barrow Neurological Institute for assistance with MRI analysis and John DeFelice for his help with organizing the sectioning of the mouse brains and H&E staining.
DS RISalud
RD Apr 7, 2025