Eric Hau

Diffuse midline glioma (DMG) is one of the most aggressive paediatric brain tumours and remains almost universally fatal despite decades of research. The defining molecular feature of approximately 80% of DMG tumours is H3K27M, which disrupts PRC2 activity and profoundly remodels chromatin architecture. Increasing evidence suggests that this epigenetic alteration not only rewires transcriptional programs but also influences tumour metabolism. Several studies indicate that H3K27M-mutant tumours exhibit altered mitochondrial metabolism, oxidative phosphorylation activity, redox regulation, and cellular stress responses, although the extent of oxidative phosphorylation dependence varies between models, tumour subtypes, and cellular states. In parallel, dopaminergic signalling has been implicated in cancer stem cell maintenance, metabolic regulation, and tumour survival across multiple malignancies, including glioma. The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses. In this review, we examine emerging connections between epigenetic dysregulation, mitochondrial metabolism, and dopamine signalling in DMG. We propose that H3K27M-driven epigenetic reprogramming may impose metabolic constraints that increase tumour reliance on mitochondrial bioenergetics and stress-buffering pathways. Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease.

Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood brain tumor. Radiotherapy remains the standard of care, but tumors recur due to radioresistance. Tumor hypoxia contributes to radioresistance, and evidence of oxidative metabolism and hypoxia-associated transcriptomic programs suggests that hypoxia may be relevant in DIPG. We therefore investigated the FDA-approved mitochondrial inhibitor atovaquone as a strategy to target oxidative metabolism and enhance radiation response in DIPG. Methods: Patient-derived DIPG cell lines were used to evaluate atovaquone by extracellular flux analysis, hypoxia and reactive oxygen species assays, clonogenic survival assays, metabolomics, and RNA sequencing. To improve brain exposure, an amorphous solid dispersion (ASD) atovaquone formulation was evaluated and tested in an orthotopic DIPG model. Results: In patient-derived DIPG cultures, atovaquone suppressed mitochondrial respiration, reduced hypoxia-associated readouts, decreased HIF-1α expression in 3D models, and enhanced radiation response. At higher concentrations, atovaquone also increased oxidative stress and enhanced the radiosensitivity of DIPG monolayers. Transcriptomics analysis revealed disruption of cell-cycle and mitotic pathways, supporting additional treatment-associated effects beyond hypoxia reduction alone. Commercial and ASD formulations showed comparable in vitro activity. In vivo, ASD atovaquone combined with radiation prolonged survival in an orthotopic DIPG model. Conclusions: Targeting mitochondrial metabolism enhances radiosensitivity in DIPG and supports mitochondrial metabolism as a potential therapeutic weakness in this disease. Its effects are associated with reduced hypoxia-related signaling and broader metabolic and transcriptional changes.

Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), are universally fatal pediatric brain tumors with no effective treatments. DIPG tumors actively utilize mitochondrial oxidative phosphorylation (OXPHOS). Inhibition of Complex I (a core OXPHOS component) by phenformin radiosensitizes DIPG in vitro and in vivo. However, phenformin’s clinical application is limited by its risk of lactic acidosis. We investigated whether co-administration of the pyruvate-dehydrogenase-kinase (PDK) inhibitor dichloroacetate (DCA) can mitigate phenformin-induced acidosis while enhancing its anti-tumor activity. Patient-derived DIPG cells (SU-DIPG17, HSJD-DIPG007, SU-DIPG-VI) were treated with phenformin (0.625 mM), DCA (25 mM) or both. Mitochondrial and glycolytic flux (oxygen consumption rate (OCR) / extracellular acidification rate (ECAR)), ATP production, Reactive Oxygen Species (ROS), cell-cycle and apoptosis were quantified alongside RNA-seq and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS)/MS metabolomics. Hypoxia was measured in neurospheres using fluorescence. Radiosensitization was assessed by γ-H2AX foci and clonogenic survival. In vivo, HSJD-DIPG007 orthotopic xenografts received phenformin (125 mg/kg/day) and DCA (250 mg/kg/day) by oral gavage for 4 weeks, alone or with focal brain-stem irradiation (2 Gy × 10); tumor immunohistochemistry and survival were recorded. DCA alone shifted glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS), reducing ECAR and intracellular lactate. When combined with phenformin, DCA significantly suppressed phenformin-induced glycolysis and ECAR while further reducing ATP. In vitro, this combination induced synergistic cell-cycle arrest, apoptosis, and ROS-induced DNA damage. Multi-omics integration revealed coordinated repression of glycolytic/ hypoxia-inducible factor (HIF) programs and diversion of glucose into redox-supportive pentose-phosphate pathways. Hypoxic staining confirmed reduced hypoxia and HIF-1α in 3D neurospheroids. The combination produced additional in vitro radiosensitization, with the phenformin + DCA + radiation triple regimen achieving the greatest γ-H2AX persistence and clonogenic kill. In mice, the triple combination schedule incurred systemic toxicity, reflected from weight loss, and did not extend survival over 4 weeks treatment. DCA effectively counteracts phenformin-induced lactic acidosis in vitro yet heightens metabolic stress and radiosensitization in DIPG cells, providing proof-of-concept that a carefully chosen metabolic partner can boost tumor control. However, weight loss in vivo limited the length of treatment schedule and optimizing dose and schedule, or selecting safer mitochondrial inhibitors with PDK blockade, will be essential next steps before determining in vivo efficacy of this metabolic strategy. Diffuse midline gliomas, including diffuse intrinsic pontine glioma, are aggressive childhood brain tumors with no effective treatments. These tumors depend on energy produced by mitochondria, making mitochondrial metabolism a promising target for new therapies. However, drugs like phenformin, which block mitochondrial metabolism, can cause dangerous lactic acid buildup, limiting their clinical use. To address this, our study combined phenformin with dichloroacetate, a drug that targets glucose metabolism and can reduce lactic acidosis. This combination successfully lowered acid buildup, disrupted tumor cell metabolism, and enhanced cancer cell sensitivity to radiation in vitro, a key treatment for these tumors. However, a pilot in vivo study highlights the challenges that will need to be overcome in dosing and toxicity when combining multiple metabolic drugs with radiation.

Diagnosis of a glioblastoma (GBM) brain tumor is associated with very poor prognosis. Currently, few preclinical models used to identify new therapies address the soft brain tissue environment and GBM mechanoresponses, which are implicated in disease progression. Understanding the GBM biomechanical landscape is critical to deriving improved preclinical models and magnetic resonance elastography (MRE) holds promise to address this gap. Due to technical and feasibility issues for MRE of patient tumors at scale, most studies only report on small cohorts of patients, thus limiting the conclusions that may be drawn from individual studies. To thus gain a better overview, we have undertaken a systematic review and meta-analysis of the reported tissue viscoelastic property values from studies of both healthy brain and brain tumors, with a particular focus on delineating measurements relative to MRE transducer vibration frequency. Based on these analyses, healthy white matter consistently appears stiffer than gray matter. Further, analyses of pooled healthy brain tissue measurements vs human GBM suggested that, overall, the GBM has the same stiffness as the surrounding healthy tissue. This contrasted with mouse models of GBM, where the tumors appear softer than brain tissue. The limited number of studies of human GBM in situ is a caveat to these conclusions and MRE analyses of larger GBM patient cohorts are urgently needed. Meanwhile, the information from this analysis can be used to guide engineering of improved preclinical models with features that recapitulate the in vivo brain tissue environment.

Background Trans Tasman Radiation Oncology Group 20.01 CHEST-RT (Chemotherapy and Immunotherapy in Extensive Stage Small cell with Thoracic Radiotherapy) is a single-arm, open-label, prospective, multicentre phase II trial study that aims to establish the safety, feasibility and describe the efficacy of incorporating thoracic radiotherapy (TRT) (concurrent or sequential) to chemotherapy and immunotherapy in patients with extensive-stage small-cell lung cancer. Methods A single arm of up to 30 evaluable participants given TRT concurrent or sequentially with chemoimmunotherapy will be enrolled. Participants should commence radiotherapy with cycle 3 or cycle 4 of chemotherapy. Those not suitable for concurrent radiotherapy due to large tumour volumes may receive sequential radiotherapy. Accounting for a 15% non-evaluable rate, up to 35 participants will be enrolled. An independent data and safety monitoring committee will review the data and assess safety and feasibility. Progression to a phase III trial would be considered feasible if ≤20% of participants experienced ≥grade 3 oesophageal toxicity and ≤10% experienced ≥grade 3 pneumonitis. This approach would be considered feasible if there is ≤20% treatment discontinuation of systemic therapy secondary to radiation toxicities and ≥75% of participants have tumour volumes that can be safely treated to a dose of 30 Gy in 10 fractions. The primary outcome of the trial is safety and feasibility, and survival and responses will be assessed as secondary endpoints. A predefined subgroup analysis of toxicity will be performed on group 1 (concurrent TRT) versus group 2 participants (consolidation TRT). Ethics and dissemination This study was approved by the Peter MacCallum Human Research Ethics Committee (HREC/73189/PMCC-2021). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and will be submitted to the approving HREC for review and approval. Trial registration numbers Australian New Zealand Clinical Trials Registry (ACTRN12621000586819) and ClinicalTrials.gov identifier (NCT05796089).

Shortening treatment time with moderately hypofractionated radiotherapy benefits patients by reducing inconvenience and costs, but its use in the definitive treatment of unresectable Stage 3 non–small cell lung cancer is controversial due to lack of level one evidence and toxicity concerns. Pivotal systemic therapy trials utilize conventionally fractionated chemoradiation at 2 Gy per fraction given over 6 weeks. In practice, 4 weeks of chemoradiation at 2.75 Gy per fraction is sometimes employed to reduce the treatment burden for selected patients, especially those who are older or have comorbidities. It is uncertain if the two fractionation regimens are similar in biological effectiveness, especially with varying systemic therapy. This systematic review aimed to collate the survival and toxicity outcomes for 4 weeks of moderately hypofractionated chemoradiation, using > 50 –60 Gy in 20 fractions. Eight studies met the eligibility criteria; seven studies were from a database search of MEDLINE, EMBASE, Cochrane Library, and Web of Science and one study was added later. Two studies were prospective randomized trials and six were retrospective cohort studies. No study included immunotherapy. The historical evidence has been limited, but emerging data is promising, especially when compared to outcomes of standard chemoradiation. Thus, further investigation of this strategy is justified.

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. 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. 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. 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.

Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.

A/Prof Eric Hau is a clinician-scientist with interest in lung and CNS tumours. His clinical and laboratory research focuses on understanding the mechanisms of radiation resistance and investigating drugs which may be utilised for radiation sensitisation to improve outcomes for patients. Associate Professor Warren Clements is an Interventional Radiologist at Alfred Health and has an Adjunct appointment with the Department of Surgery, Central Clinical School, Monash University. A/Prof Clements completed post-fellowship subspecialty training in Interventional Radiology, consolidated by completion of the EBIR certification. A/Prof Clements is actively involved in medical research with over 80 peer-reviewed publications, and has presented his research at national and international conferences. He is an Associate Editor for JMIRO and editorial board member of both CVIR and CVIR Endovascular. He volunteers his time for RANZCR as a member of the Interventional Radiology Committee and as an editorial board member for RANZCR's Inside Radiology website. A/Prof Clements has a keen interest in education and training, and is the supervisor of Intern Training in the Radiology Department. Dr. Joseph (Joe) Sia is a Consultant Radiation Oncologist at the Peter MacCallum Cancer Centre, Melbourne, Australia. He obtained his medical degree from the University of Otago, New Zealand and completed his radiation oncology training in Melbourne in 2017. He then undertook a laboratory-based PhD in tumour immunology at the University of Melbourne, which was awarded in 2020.

Objective: The purpose of this narrative review is to survey the current literature and provide treatment recommendations for the management of patients with brain metastases ( BMs) from small cell lung cancer (SCLC). Background: BMs are very common in patients with SCLC and management has changed significantly in recent years. Radiation techniques and systemic therapies have evolved and this review will highlight these recent studies and implications on clinical practice. Methods: This narrative review covers prophylaxis and treatment of established BMs in patients with SCLC. Studies included are based on Medline, PubMed, Google scholar searches, abstracts from conference proceedings and references from published papers. Conclusions: Radiation therapy continue to have an important role in the prophylaxis and treatment of patients with BMs. Radiation technologies have resulted in significant reduction of toxicities and improved quality of life (QoL). There continues to be many unanswered questions and results of currently accruing trials will hopefully fill some of these gaps and refine the role of radiation therapy in the management of this condition.