ESTRO 2024 - Abstract Book

S63 ESTRO 2024 effectively, future developments in this discipline will involve improving predictive models and incorporating patient reported outcomes. In conclusion, addressing treatment-related toxicities in radiation oncology is a complex process that calls for proactive surveillance, individualised intervention plans, and a thorough understanding of the root causes. In the current era of radiation therapy, maintaining cross-disciplinary collaboration is essential to improving patient outcomes and quality of life. Invited Speaker

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Targeting redox metabolism to enhance radiation response

Marianne Koritzinsky

University Health Network, Princess Margaret Cancer Centre, Toronto, Canada

Abstract:

Metabolic deregulation serves to support the high biosynthetic needs of cancer cells. It also ensures cellular redox homeostasis despite high production of reactive oxygen species (ROS) as a byproduct of high proliferation and metabolism. High activity of anti-oxidant systems relies on abundant cellular cysteine pools, which supports biosynthesis of small molecule antioxidants such as glutathione. Cancer cells achieve this by having high cystine uptake and transsulfuration activity, as well as through silencing of cysteine catabolism pathways. Furthermore, cancer cells become dependent on expression of various proteins that are key to antioxidant defense systems. As such, the ability of cells to metabolize ROS can represent a cancer-specific vulnerability associated with a therapeutic window. Inability to contain ROS abundance leads to toxicity due to damage of macromolecules such as lipids and DNA. Redox metabolism is also key to low LET radiation response, where ROS initiate a majority of DNA damage, and damage restitution through sulfhydryl reactions compete with oxygen for damage fixation. As such, targeting ROS metabolism can offer a strategy for radiosensitization. The spectrum of biochemical DNA damage and cytosolic release is also affected by disruption of redox homeostasis, which can potentially enhance immunogenicity of combination treatments.

This presentation will review the concepts introduced above, and provide examples of therapeutic strategies that leverage disruption of redox metabolism.

• Metabolic deregulation is a hallmark of cancer • Metabolic deregulation is key to cancer cell redox homeostasis • Redox homeostasis is a cancer-specific vulnerability • Targeting redox homeostasis can be associated with a therapeutic window • Redox balance is a determinant of intrinsic radiation response • Disruption of redox balance can exacerbate DNA damage from radiation • Disruption of redox balance can enhance the release of immunogenic cytosolic DNA • Targeting pathways that regulate metabolism of reactive oxygen species can cause direct cancer cell death and stimulate immunogenicity