Abstract IA007: Targeting the hypoxia-induced DDR to improve radiotherapy response

Abstract

Abstract Regions of hypoxia (insufficient oxygen) occur to some extent in most if not all solid tumors. Within hypoxic regions the levels of oxygen are heterogeneous and can reach near anoxic levels, often referred to as radiobiological hypoxia. Cells experiencing radiobiological hypoxia are significantly more resistant to radiation-induced DNA damage and negatively impact radiotherapy response. A number of clinical studies have demonstrated that hypoxia is a significant indicator of poor patient response. Radiobiological hypoxia, unlike milder hypoxic conditions, leads to a robust DNA damage response although interestingly, this occurs in the absence of detectable DNA damage. Instead, the hypoxia-induced DDR has been attributed to the accumulation of replication stress. Previously, we demonstrated that hypoxia-induced replication stress originated from reduced nucleotide availability due to the oxygen-dependency of ribonucleotide reductase. More, recently we have implicated the accumulation of R-loops in contributing to not only the hypoxia-induced DDR but also transcriptional stress. Numerous factors play key roles in maintaining R-loops and preventing the accumulation of DNA damage including the DNA/RNA helicase SETX. Using SETX has an exemplar, we have demonstrated that targeting R-loop factors leads to increased DNA damage in hypoxic conditions. Currently, we are testing the hypothesis that hypoxia specific R-loop factors are potential therapeutic targets which offer the possibility of increasing the radiosensitivity of hypoxic cells. Citation Format: Ester Hammond. Targeting the hypoxia-induced DDR to improve radiotherapy response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA007.