ESTRO 38 Abstract book

S237 ESTRO 38

demonstrate that sensitivity to 2-DG monotherapy is increased in tumor lines that are highly glycolytic, and that 2-DG enhances the efficacy of cisplatin chemotherapy and radiation in glycolytic tumor cells. When 2-DG is combined with L-buthionine sulfoximine (BSO), an inhibitor of glutathione biosynthesis, and auranofin (AUR), a thioredoxin reductase inhibitor, glycolytic cervical cancer cells are unable to proliferate. Detailed analysis of intracellular redox parameters indicates that these effects are mediated primarily by increases in intracellular reactive oxygen species, which can promote autophagic and non-autophagic forms of cell death depending on the oncogenic context. In cervical tumor models in the mouse, this drug strategy can be used to limit tumor growth for highly glycolytic cancers and to radio-sensitize cancers that display intermediate levels of Warburg-related glucose metabolism. Consistent with our hypothesis, combined treatment with 2-DG, BSO and AUR is more effective as a radio-sensitizer in vivo that 2-DG alone. Most recently, we have found that glutamine deprivation or treatment with glutaminase inhibitors can also be used to promote increases in intracellular oxidative stress that facilitate radiation therapy efficacy. SP-0456 Sex differences in cancer metabolism: implications for therapy J. Ippolito 1 1 Washington University School of Medicine, Radiology, Saint Louis, USA Abstract text There is a sex disparity in many cancers throughout the body where males have a higher incidence and mortality compared to females. Moreover, these effects are independent of age suggesting that cell-intrinsic phenomena, rather than the effects of sex hormones, may play a key role in this clinical phenotype. Metabolism is one potential factor underlying this disparity where nutrient uptake and metabolism are enhanced in males relative to females beginning at the earliest stages of embryogenesis and are carried into adulthood. Because of the established inverse correlation between enhanced glucose metabolism and patient survival in many cancers, we hypothesized that sex differences in central carbon metabolism underlie sex differences in cancer patient survival. We developed a data mining algorithm using The Cancer Genome Atlas (TCGA) to identify metabolic gene expression patterns that correlated with poor sex-specific outcomes. We applied this algorithm to the lower grade glioma (LGG) transcriptome and identified numerous enzymes involved in glycolysis, glutamine-fueled tricarboxylic acid (TCA) cycle metabolism, and oxidative phosphorylation that uniquely identified men, but not women, with poor outcomes. We validated these findings using an established mouse model for sex differences in gliomas, the Nf1 -/- DNp53 model, where transformed mouse astrocytes are deficient for neurofibromin 1 ( Nf1 ) and express dominant negative p53 ( DNp53 ) protein. We identified that a critical metabolic sex difference was glutamine-fueled TCA cycle metabolism that was significantly higher in transformed male astrocytes. We also identified that transformed male astrocytes were more susceptible to inhibition of glutamine metabolism with glutaminase inhibitors compared to females. Together, these findings highlight sex-specific dependencies of specific nutrients and metabolic pathways on tumor growth that may potentially be exploited for therapy. Moreover, clinically-relevant metabolic imaging modalities such as fluorodeoxyglucose- PET, fluoroglutamine-PET, or hyperpolarized carbon-13 MRI may identify prognostic sex differences in patients.

SP-0458 Targeting metabolism to sensitize hypoxic tumor cells M. Koritzinsky 1 1 University Health Network, Princess Margaret Cancer Centre, Toronto, Canada Abstract text Tumor hypoxia has long been recognized as a limiting factor for radiotherapy response due to the strong radiosensitizing effect of oxygen. Although randomized clinical trials have demonstrated some benefit of increasing the oxygen supply or replacing oxygen with radiosensitizers during radiotherapy, these strategies have not resulted in widespread clinical adoption. Over the last few years, a common theme has emerged from experimental studies, highlighting the potential for various clinically approved drugs to enhance tumor oxygenation through inhibition of the oxygen consumption of tumor cells close to blood vessels. These studies have hence led to several ongoing randomized clinical trials in which these drugs are repurposed to enhance tumor oxygenation during radiotherapy. A complimentary approach to sensitize hypoxic tumors is to target hypoxia adaptation mechanisms that render cancer cells vulnerable to the lack of oxygen. Many aspects of metabolism are altered or specifically required under hypoxic conditions, including the cellular metabolism of reactive oxygen species (ROS). Cancer cells frequently have high ROS production due to deregulated proliferation and metabolism. Hypoxia further increases overall cellular levels of ROS, and reoxygenation triggers substantial ROS bursts. Together, this renders tumor cells vulnerable to targeting anti-oxidant defense systems. Here we will present data demonstrating that the protein peroxiredoxin 4 (PRDX4) is essential in both normoxia and fluctuating oxygen conditions in vitro and in experimental tumor models. Loss of PRDX4 leads to increase ROS and DNA damage, resulting in cell toxicity and radiosensitization. These data support the potential for combining disruption of redox homeostasis with radiotherapy for improved therapeutic ratio. SP-0459 Clinical status of MR-integrated photon therapy L. Boldrini 1 1 Fondazione Policlinico Universitario "A. Gemelli" Irccs, Radiation Oncology, Rome, Italy Abstract text The introduction of MR integrated delivery units represents one of the most significant and promising innovations of the last years in radiotherapy delivery technology. The advantages assured by the better visualization of the therapy volumes allowed by on board MR imaging and the possibility to use active gating and motion management solutions embedded in this novel workflow need to be further explored and quantified both from a technical and a clinical perspective. Aim of this talk is to describe the current clinical status of the MR- integrated photon radiotherapy and to present the clinical evidence to date available. Its most common applications will be reported, ranging from the patient selection methods to the choice of the most appropriate therapy delivery protocol. Furthermore, the possibility to implement innovative hypothesis generating approaches (movement management, radiomics, new delivery techniques) in clinical MR-integrated radiotherapy will be presented. Joint Symposium: ESTRO-ESR: Current status and future challenges in MR-integrated radiotherapy

SP-0457 Hypoxia-induced Replication Stress TBC