ESTRO 2024 - Abstract Book

S113

Invited Speaker

ESTRO 2024

Abstract:

For over hundred years, it has been well established that hypoxia attenuates the efficacy of radiotherapy. To enhance the therapeutic window of irradiation, targeting or alleviating tumor hypoxia may be a relatively tumor-specific approach for radiosensitization, thereby increasing treatment efficacy and attenuating toxicity. A multitude of different approaches has been applied over the years, including carbogen breathing, hypoxia-activated prodrugs and oxygen mimetics, which in combination with radiotherapy is often successful. However, hypoxia is now also known to foster an immune-suppressive tumor microenvironment, which would likely not be reversed by short term hypoxia alleviation. Therefore, to enhance the anti-tumor immune response induced by irradiation, an approach leading to long-lasting effects on hypoxia is required. I will present data indicating how tumor cells display a widely plastic metabolism, switching between glycolysis and oxidative phosphorylation (OXPHOS) depending on availability of oxygen and glucose. Inhibition of glycolysis or glutaminolysis variably radiosensitizes cancer cell lines in vitro. Under more or less physiological glucose levels, several cancer cell lines exhibit considerable oxygen consumption, leading to hypoxic cores in spheroids, even when grown at 20% oxygen. Reducing oxygen consumption could therefore be an effective way alleviate hypoxia in tumors for longer time periods, i.e. days to weeks. Inhibition of OXPHOS can be accomplished using an array of different inhibitors, each with specific efficacies and side-effects. I will discuss the pros and cons of several inhibitors such as atovaquone, metformin, IACS10759 and tamoxifen, and also address novel developed mitochondria targeting compounds. However, by inhibition of mitochondrial complexes in the electron transport chain, OXPHOS inhibition will also induce reactive oxygen species (ROS). ROS are important and tightly regulated messenger molecules, and may also induce DNA damage and anti-tumor immune responses. On the other hand, chronic ROS induction will elicit an NRF2 mediated protective cellular response in the form of anti-oxidants, which in turn would counter ROS inducing treatments such as radiotherapy. These anti-oxidants are also generated via glucose metabolism, most notably by NADPH generation in the pentose-phosphate side-pathway of aerobic glycolysis. NADPH plays a crucial role in antioxidant protection by facilitating the reduction of oxidized glutathione and potentially functioning directly as an antioxidant. In conclusion, glucose metabolism is important in establishing intrinsic cellular radiosensitivity. Specific glucose metabolism pathways can be targeted to enhance radiotherapy efficacy and combined with immunotherapy. However, inhibition of aerobic glycolysis or mitochondrial respiration has both positive and negative consequences that need to be addressed before full clinical application will be feasible.

3509

What every physicist should know about commissioning TG-43- and model-based treatment planning systems in brachytherapy

Marisol De Brabandere