title: The radiobiological targets of SBRT: tumor cells or endothelial cells?
abstract: The development of stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) techniques has revolutionized the practice of radiation oncology. The radiobiological targets that alter the therapeutic response to SBRT remain a subject of debate. The prevailing perspective has been that the radiation-induced damage to endothelial cells and changes in microvasculature facilitate tumor response to SBRT. A provocative study by Moding et al. (PMID: 25761890), challenged this notion by elucidating the role of tumor cells versus endothelial cells in mediating sarcoma eradication following high-dose SBRT. Using dual recombinase technology, they generated primary sarcomas in genetically engineered mouse models (GEMMs). They also modulated the apoptotic pathway and radiosensitization profile using targeted mutations in either tumor cells or endothelial cells. Unlike transplanted tumor models, the findings here suggest that deletion of the pro-apoptotic gene Bax or of the DNA-damage response gene ATM in endothelial cells did not result in tumor eradication to high dose SBRT, despite extensive endothelial cell death. On the other hand, genetic targeting of ATM gene in tumor cells achieved local sarcoma control and tumor eradication. These findings imply that tumor cells rather than endothelial cells act as prime targets affecting a tumor eradication response to SBRT. The translational implications of these findings are of great potential significance. When targeting endothelial cells, delivery of SBRT irradiation can only result in tumor growth delay. The benefit of targeting ATM in this setting will be radiation dose dependent. Curative intent, tumor eradication and local control, on the other hand, are only possible by targeting tumor cells with high dose SBRT (50 Gy in 1 fraction) and with radiosensitization by ATM deletion. In the absence of radiosensitization, only palliation is possible with high dose SBRT. Whether these provocative findings can be extrapolated to other translational tumor models or proved valid in clinical trials remains the subject of future studies. The mechanisms by which tumors compensate to SBRT's endothelial cell damage, such as new vascular recruitment, and/or recruitment of other immune and stromal components, are also critical questions for the field of radiobiology to address. Such mechanistic understanding of the key cellular players mediating SBRT response in a model system that recapitulates human disease will be essential in designing targeted radiosensitizers ultimately aimed at improving the therapeutic ratio.
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Sana D
authors.initials: SD
authors.lastname: Karam
authors.affiliation: Department of Radiation Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Bhatia
keywords: ATM; Stereotactic body radiation therapy (SBRT); dose; endothelial cell death; hypofractionated; radiosensitization; stereotactic ablative radiotherapy; stereotactic radiosurgery (SRS)