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Radiotherapy remains a common treatment modality for cancer despite skeletal complications. However, there are currently no effective treatments for radiation-induced bone loss, and the consequences of radiotherapy on skeletal progenitor cell (SPC) survival and function remain unclear. After radiation, leptin receptor–expressing cells, which include a population of SPCs, become localized to hypoxic regions of the bone and stabilize the transcription factor hypoxia-inducible factor-2α (HIF-2α), thus suggesting a role for HIF-2α in the skeletal response to radiation. Here, we conditionally knocked out HIF-2α in leptin receptor–expressing cells and their descendants in mice. Radiation therapy in littermate control mice reduced bone mass; however, HIF-2α conditional knockout mice maintained bone mass comparable to nonirradiated control animals. HIF-2α negatively regulated the number of SPCs, bone formation, and bone mineralization. To test whether blocking HIF-2α pharmacologically could reduce bone loss during radiation, we administered a selective HIF-2α inhibitor called PT2399 (a structural analog of which was recently FDA-approved) to wild-type mice before radiation exposure. Pharmacological inhibition of HIF-2α was sufficient to prevent radiation-induced bone loss in a single-limb irradiation mouse model. Given that ~90% of patients who receive a HIF-2α inhibitor develop anemia because of off-target effects, we developed a bone-targeting nanocarrier formulation to deliver the HIF-2α inhibitor to mouse bone, to increase on-target efficacy and reduce off-target toxicities. Nanocarrier-loaded PT2399 prevented radiation-induced bone loss in mice while reducing drug accumulation in the kidney. Targeted inhibition of HIF-2α may represent a therapeutic approach for protecting bone during radiation therapy. Editor's summary: Radiotherapy frequently leads to bone loss. Here, Guo and colleagues explored the role of hypoxia signaling through HIF-2α in skeletal progenitor cells as a negative regulator of bone mass after radiotherapy in mice. Selective knockout of HIF-2α in leptin receptor-expressing skeletal progenitor cells rescued mice from decreased bone mass after total body irradiation. Pharmacologic inhibition of HIF-2α improved bone integrity; however, systemic treatment caused off-target effects. Therefore, a bone-targeting nanocarrier was developed to deliver localized HIF-2α inhibition, which alleviated radiation-induced bone loss without systemic off-target effects. This represents a promising targeted strategy that awaits further clinical validation. —Molly Ogle [ABSTRACT FROM AUTHOR]

Simple Summary: The ability of ultra-high dose rate FLASH radiation therapy (RT) to reduce normal tissue toxicity without affecting tumor response relative to conventional dose rate radiation therapy could fundamentally change the way we treat cancer. However, this field is still in its early stages, and the magnitude of the sparing effect between treatment centers differs greatly for reasons as yet unknown, which has put the robustness of the effect into question. In this study, we show that when similar irradiation beam parameter settings are used, the induced sparing effect is robust and reproducible across institutions. These settings should serve as a reference for further optimization of the FLASH effect. FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used. [ABSTRACT FROM AUTHOR]