Leveraging mitochondrial function to combat radiation therapy-induced microvascular disease

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Every year, an estimated 20,000 of the 200,000 veterans treated for cancer at a Veterans Health Administration facility receive radiation therapy (RT) as part of their treatment plan. As chemo- and radiotherapies become more effective, patients are living long enough to develop late adverse effects of radiation, such as heart failure and cognitive decline after chest and brain irradiation, respectively. These disorders, termed “normal tissue injury” (NTI), are thought to result from acute radiation damage to the microvascular endothelium of vessels supplying the otherwise healthy tissues that surround the targeted cancer. While later-stage NTI has been characterized by decreased capillary density, ischemia, and loss of normal tissue function, the early damage responses which drive these pathologies remains unclear. Chronic oxidative stress, initiated by the burst of superoxide and hydroxyl radicals during ionizing radiation exposure, is a potential driver of progressive damage to the microvascular endothelium. Associations between these pathways and the decreased blood flow observed after RT have yet to be established. In order to develop preventative measures and mitigators, early markers of vascular response to RT must be identified, and a relationship established between them and the late vascular pathologies observed with NTI. The objective of the proposed project is to dissect the role of blood flow in the development of normal tissue injury after radiation therapy, and to determine whether mitigation of oxidative stress can diminish or eliminate these changes. Chronic oxidative stress in the vascular endothelium has been associated with diminished vasodilatory capacity and endothelial dysfunction, which may then result in decreased blood flow after RT. Antioxidants like pharmacological ascorbate (P-AscH-) have been successfully deployed to mitigate vascular endothelial dysfunction in models of vascular disease like diabetes and hypertension; furthermore, in clinical studies of cancers like glioblastoma multiforme, treatment with P-AscH- has been shown effective at improving progression-free and overall survival. We postulate that chronic oxidative stress initiated during RT is responsible for early perfusion defects, which progress to ischemia and loss of normal tissue function. Our central hypothesis is that decreased blood flow, which may be mitigated by administration of P-AscH-, precedes cognitive dysfunction after radiotherapy. This hypothesis is supported by pilot data showing decreased blood flow as early as 14 days after radiation exposure, before a decrease in cognitive function was detected 30 days after irradiation of a single hemisphere. The precision targeting provided by our state-of-the- art small animal irradiator enables dose delivery to a single hemisphere, such that the contralateral hemisphere can be used as an internal control. Blood flow and tissue oxygenation will be measured in each hemisphere using laser speckle flowgraphy and oxygen enhanced multispectral optoacoustic tomography, respectively. The aims of our proposed studies are to 1) Determine whether decreases in blood flow precede cognitive dysfunction after RT, and 2) Determine the extent to which P-AscH- protects against radiation-induced perfusion defects. The rationale of the proposed project is that a characterization of early hemodynamic response to radiation will enable the development of preventatives and mitigators of radiation-induced vascular injury. Upon the successful completion of these studies, we will have provided evidence for whether early variations in blood flow can be associated with radiation-induced oxidative stress, and whether these changes predict late loss of normal tissue function. Identifying the sequence of events and establishing methods for detection will facilitate the development of novel therapeutics or prevention strategies which will ultimately improve survivor quality of life.