Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma

Han Shen; Faiqa Mudassar; Shiyong Ma; Xingyu Wang; Sandy Nguyen; Neha Bal; Quy-Susan Huynh; Dongwei Wang; Cecilia Chang; Prunella Ing; Winny Varikatt; Joey Lai; Brian Gloss; Jeff Holst; Geraldine M O'Neill; Harriet Gee; Kristina M Cook; Eric Hau

doi:10.1093/neuonc/noae255

Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma

Neuro Oncol. 2024 Nov 22:noae255. doi: 10.1093/neuonc/noae255. Online ahead of print.

Authors

Han Shen^{1

2}, Faiqa Mudassar^{1

2}, Shiyong Ma³, Xingyu Wang³, Sandy Nguyen¹, Neha Bal^{1

2

4}, Quy-Susan Huynh¹, Dongwei Wang¹, Cecilia Chang¹, Prunella Ing¹, Winny Varikatt², Joey Lai⁵, Brian Gloss⁵, Jeff Holst⁶, Geraldine M O'Neill^{2

7}, Harriet Gee^{1

2

8

9}, Kristina M Cook^{1

2

4}, Eric Hau^{1

2

8}

Affiliations

¹ Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, NSW, Australia.
² Faculty of Medicine and Health, Sydney Medical School, The University of Sydney, NSW, Australia.
³ Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, The Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
⁴ Charles Perkins Centre, The University of Sydney, NSW, Australia.
⁵ Westmead Research Hub Core Facilities, Westmead Institute for Medical Research, NSW, Australia.
⁶ School of Biomedical Sciences, UNSW Sydney, NSW, Australia.
⁷ Children's Cancer Research Unit, The Children's Hospital at Westmead, NSW, Australia.
⁸ Western Sydney Radiation Oncology Network, NSW, Australia.
⁹ Children's Medical Research Institute, Westmead, NSW, Australia.

PMID: 39575457
DOI: 10.1093/neuonc/noae255

Abstract

Background: Diffuse Intrinsic Pontine Gliomas (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides temporary symptomatic relief due to radioresistance. While hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic. DIPGs often contain histone mutations, which alter tumor metabolism and are also associated with radioresistance. Our objective was to identify the metabolic profiles of DIPG cells, detect hypoxia signatures, and uncover metabolism-linked mechanisms of radioresistance to improve tumor radiosensitivity.

Method: Using DIPG models combined with clinical datasets, we examined mitochondrial metabolism and signatures of hypoxia. We explored DIPG reliance on mitochondrial metabolism using extracellular flux assays and targeted metabolomics. In vitro and in vivo models were used to explore the mechanisms of targeting mitochondrial bioenergetics and hypoxia for radiosensitization. Treatment-induced transcriptomics and metabolomics were also investigated.

Results: Comprehensive analyses of DIPG cells show signatures of enhanced oxidative phosphorylation (OXPHOS). We also identified increased expression of specific OXPHOS related genes and signatures of hypoxia gene expression in datasets obtained from DIPG patients. We found the presence of hypoxia in orthotopic mouse models bearing DIPG tumors. These findings enabled us to develop a proof-of-concept treatment strategy to enhance radiosensitivity of DIPGs in vitro and in animal models.

Conclusion: DIPG cells rely on mitochondrial metabolism for growth, and targeting mitochondria disrupts bioenergetics, alleviates hypoxia, and enhances radiosensitivity. These findings warrant further exploration of OXPHOS inhibition as a radiosensitizing strategy for DIPG treatment.

Keywords: diffuse intrinsic pontine gliomas; hypoxia; mitochondria; radiotherapy.