Targeting the HIF-2 Signaling Pathway as a Radioprotective Strategy for Bone

PROJECT SUMMARY While radiation therapy effectively eliminates malignant cells, damage to healthy tissue surrounding tumors remains a persistent clinical issue. Indeed, cancer patients who receive radiation treatment have an increased risk for fracture when compared to those who undergo the same treatment regimen but who are not subjected to radiotherapy. Unfortunately, the use of antiresorptive agents such as bisphosphates does not significantly reduce insufficiency fractures for this patient population. For these reasons, our long-term goal is to identify unique cellular and molecular mechanisms that can be therapeutically exploited for the radioprotection of bone. Notably, the bone microenvironment (BME) is characterized by low oxygen tension or hypoxia. In response to this external stimulus, many cell types in the BME activate hypoxia inducible factor (HIF) signaling to facilitate cell survival. While activation of the HIF signaling pathway is required to maintain healthy bone, the contribution of hypoxia/HIF signaling during radiation induced bone damage has not been well defined. Intriguingly, we show irradiated bones show a decrease in multipotent mesenchymal progenitors (MMPs) when compared to non- irradiated controls. Moreover, preliminary data shows that MMPs are found in hypoxic regions and respond to hypoxia by stabilizing HIF-2. Strikingly, while conditional ablation of HIF-2 in a population of MMPs did not alter bone homeostasis, it did serve to protect against bone loss after radiation exposure. For these reasons, our overarching hypothesis is that genetic and pharmacological inhibition of HIF-2 will serve as a radioprotective mechanism to ameliorate bone damage after radiation exposure, in part, by maintaining the number of MMPs that can functionally contribute to bone after stress induced damage. To test our hypothesis, we will utilize a combination of genetically engineered mouse models, in vitro cell culture experiments, and novel pharmacological approaches to inhibit the HIF-2 signaling pathway in the BME. Currently, there are no FDA approved agents to mitigate radiation induced bone loss, hence these studies will not only expand our fundamental knowledge of bone biology but will also fill an unmet clinical need to identify therapeutic targets which will ameliorate bone damage after radiotherapy.