ESTRO 2024 Radiobiology Track – Pre-meeting course

Course directors:

• Anthony Chalmers, radiation oncologist, University of Glasgow, UK
• Julie Schwarz, radiation oncologist, Washington University St. Louis, USA
• Conchita Vens, radiation biologist, University of Glasgow, UK

Course Objectives

The biology pre-meeting course was designed to enable a basic understanding of metabolism and metabolic changes that are frequently observed in cancers. Also, it addressed how these changes influence cellular and tumour responses to radiotherapy and how metabolism is affected by radiotherapy. Numerous drugs that target metabolism have been developed and are in the pipeline, but few have reached clinical testing in combination with radiation. It is important, therefore, to increase awareness and understanding of radio-metabolomics, and the course was focused strongly on how metabolism can be targeted in combination with radiotherapy.

Introduction to Metabolism

Yuanyuan Zhang and Julie Schwarz introduced the topic of metabolism in normal and tumour tissues. Altered metabolism is a hallmark of cancer and cancer progression. This is exemplified by the Warburg effect, in which cancer cells show enhanced glucose utilisation via glycolysis in the presence of oxygen. Consequently, accumulation of oncometabolites, increased oxidative stress, and modulation of the microenvironment are common tumour traits. Most genetic mutations, many of which are seen in cancers, affect metabolism. These include mutations in KRAS, BRAF, EGFR, and IDH1/2 genes. Many of them are actionable, making metabolism a feasible target for therapeutic intervention.

Best Practices

Mechanistic studies to identify metabolic targets are challenging to perform, and we got advice on best practices for in-vitro studies. Dr Schwarz emphasised the importance of culturing cells under realistic conditions with regard to oxygen, nutrients and drug concentrations. An overview of common molecular biology approaches that can be taken in metabolic studies was provided, and the need for 3D culturing and lengthened time assessments to address metabolic adaptation and resistance was highlighted.

Metabolism and DNA Repair

Metabolism regulates cellular processes like repair of DNA damage and thereby radiation responses. Dan Wahl mentioned nucleotides, a crucial metabolite in repair, as the best-understood regulators of radiation response. Several antimetabolite radiosensitisers that regulate levels of deoxy-nucleotides and slow down DNA repair are standard-of-care for some cancer types. Another example is antioxidants, including glutathione, which reduces the level of DNA damage and can be targeted by glutaminase inhibitors. Energy and adenosine triphosphate (ATP) levels are important for DNA repair, and mitochondrial drugs such as metformin and atovaquone were mentioned. Dr Wahl also mentioned guanosine triphosphate (GTP) as a critical nucleotide for DNA repair and discussed the use of an inhibitor of GTP-mediated signalling to target DNA repair under genotoxic stress.

Effect of Metabolism on Radiotherapy

The effect of metabolism on radiotherapy was covered by Natividad Gomez-Roman. Irradiated cells require ATP to regenerate. This happens through the repair of DNA and membranes, and the building of antioxidant defence as a protection against reactive oxygen species (ROS). Radiotherapy induces metabolic rewiring to increase the levels of nucleotides, amino acids, lipids and cholesterol. This leads to an increase in rates of glycolysis, the pentose-phosphate pathway, lactate flux from the cells, and extracellular acidification. Activation of the cholesterol pathway to protect against apoptosis was also mentioned, and cholesterol lowering drugs (e.g. AY9944) are under investigation as strategies to increase rates of cell death after radiation treatment.

Targeting Metabolism

Johann Matchke gave a separate lecture on the targeting of metabolism. He presented a systematic analysis of cell cultures to explore the interplay between metabolism, DNA repair and cell survival after radiation. The value of biostatistical modelling to determine radiation-induced metabolic bottlenecks was demonstrated. The mitochondrial citrate transporter SLC25A1 plays a role in the repair of double-stranded breaks. Dr Matchke identified this protein as a major determinant of radiosensitivity and a possible therapeutic target.

Metabolism and the Tumour Microenvironment

After lunch, the programme was directed towards in-vivo issues, imaging technologies to assess metabolism in tumours and clinical trials. Marianne Koritzinsky presented an overview of the tumour ecosystem, with cancer cells, immune cells and stroma. She highlighted the deprived tumour microenvironment with gradients in levels of oxygen, nutrients, pH and lactate. The deprived microenvironment shapes metabolic pathways in cancer cells and their interaction with immune and stroma cells. These factors cause radioresistance and suppress the immune system, and represent therapeutic targets. A novel oxygen sensor, cysteamine dioxygenase, was presented. This protein protects cells against mitochondrial hyperactivity and ROS under hypoxic conditions.

Imaging Techniques

Two lectures were devoted to imaging. The advantage of imaging is the ability to capture the spatiotemporal heterogeneity in tumour metabolism. Fluorodeoxyglucose positron emission tomography (FDG-PET) is used widely to visualise glucose uptake. David Lewis presented new PET tracers that could be used to assess metabolic features like antioxidant responses and glutamine uptake in a preclinical setting. Moreover, hyperpolarised MRI can be used to visualise metabolites such as pyruvate, lactate and bicarbonate, and glucose and glutamate can be assessed through the use of deuterium MRI. Daniela Thorwarth discussed methods for clinical use, including FDG-PET, MR spectroscopy, and chemical exchange saturation transfer imaging. She highlighted FDG-PET as the currently best option and demonstrated the use of this technique to visualise metabolic responses after radiotherapy combined with immunotherapy. This opens up new applications of FDG-PET in combination therapies. The need for technologies to integrate in-vivo imaging with ex-vivo spatial information including histology and spatial metabolomics and transcriptomics was emphasised.

Clinical Trials

The final lecture, by Adam Peters, gave an overview of clinical trials in which metabolic targeting agents have been tested in combination with radiotherapy. There have been only a few trials, in which glutaminase and inhibitors of oxidative phosphorylation have been tested. The value of drug repurposing was emphasised, due to a short development time and inexpensive use of the drugs. Such drugs should be tested in parallel with the development of new drugs.

General Discussion

The course ended with a general discussion on how to bring more metabolic targeting agents into clinical trials with radiotherapy. Major challenges that were mentioned included difficulties in gaining interest from the pharmaceutical industry and its support for radio-metabolomic research; increased awareness is required from pharma. As scientists, we should document better the drug effects on normal tissues, and address time-schedule aspects in relation to radiotherapy and the effects of fractionation.

Conclusion and Feedback

This course provided an update on the many areas of research that are being investigated in the field and highlighted important knowledge gaps regarding further clinical applications. The course attracted a diverse group of people ‑ physicists, radiation therapists and oncologists in addition to biologists ‑ which reflected a broad interest in the field. The feedback from course participants was very positive, as reflected by scores and comments in a survey that could be completed after the course. All lectures received a high mean score of between 4 (very good) and 5 (excellent), and the overall impression, including the quality and relevance of the course and suitability of the format, received the same high score. Comments included that this was a well-organised course with great lectures.

Professor Heidi Lyng

Department of Radiation Biology

Oslo University Hospital

Norway

Email: heidi.lyng@rr-research.no