UC Irvine

Radiotherapy has long been used to control tumor growth by causing ionization of cellular macromolecules including DNA, RNA, lipids and proteins, leading to lethal or sublethal damage to a cell. Typically, convention radiotherapy (CONV-RT) is delivered at a dose rate between 0.07–0.1 Gy⋅s−1 and fractionated over an extended treatment plan (1 -2 months), allowing healthy normal tissue to mend sublethal damage while repair-compromised tumor tissue accumulates damage. Previous studies have identified that fractions under 2 Gy are required to reduce long-term neurocognitive damage1. These normal tissue dose tolerances limit the therapeutic benefit of radiotherapy. A recent breakthrough in radiation delivery modalities have shown that using ultra-high dose rates (>100 Gy⋅s−1), or ‘FLASH’ irradiation, can reduce cognitive damage, spare normal tissue injury, and minimize harm to critical systems like the blood brain barrier (BBB), all while maintaining isoefficient tumor control2–4. This new radiation modality has the potential to greatly extend the therapeutic benefit of radiotherapy while limiting the unintended neurological sequelae that are frequently caused by treatment.

At this point, our lab has produced substantial evidence that FLASH irradiation reduces damage done to the CNS normal tissue, protecting the homeostasis, and potentially reducing the onset and severity of late radiation-injury in brain tumor survivors subjected to cranial radiotherapy. Experiments performed by ourselves and collaborators have examined the FLASH effect using preclinical models of fish, rodents, cats, and mini-pigs2,5–8 and has successfully been used clinically in a single patient to treat multiresistant CD30+ T-cell cutaneous lymphoma4. While a plethora of data is available on the FLASH effect, the underlying mechanisms are still not fully understood. Our lab has shown that oxygenation levels of the tissue play a vital role in radiation induce tissue damage through mitigation of reactive oxygen species (ROS)2; however, there are likely other key mechanisms at play. The importance of tissue oxygenation and the role the BBB plays in maintaining CNS homeostasis are why we consider the vasculature to be a key element in deciphering the FLASH effect.

The Limoli lab has been publishing regularly on the benefits of FLASH irradiation in pre-clinical models for the last 4 years, highlighting the normal tissue sparing effects in the CNS. My work in particular has focused on the effect of both CONV and FLASH irradiation on the normal tissue and the BBB. I performed initial experiments utilizing FLASH and CONV radiation to determine effects on the BBB at early timepoints which led to a publication in Radiation Research9. Following this, I spent time exploring the literature behind CNS vasculature, radiotherapy, and new experimental therapeutic techniques which culminated into a published review in Free Radical Biology and Medicine10. I have used this rationale to examine the cognitive and vasculature effects of FLASH on juveniles11, a particularly radiation susceptible population. Results from the juvenile model have guided us to explore the neurological mechanistic basis of the effect we find in an adult model while simultaneously testing the threshold of dose tolerance. Further experiments on a similar cohort of adult animals to measure blood flow and tissue oxygenation levels using spatial frequency and domain imaging. Results from this publication are expected to be concluded soon. The objective of this dissertation is to, in part, determine if the normal tissue sparing effect of FLASH irradiation reduces radiation-induced pathology of the BBB, further explicate the neuro-mechanistic basis of cognitive protection and determine the effects on tumor vascularization. Results produced from this body of work will not only provide additional justification for clinical translation, but it may also help illuminate key mechanistic differences between cancer and normal tissue that may one day be used for therapeutic gain.

My field of focus has been the effects of ultra-high dose rate FLASH radiotherapy in pre-clinical models. In particular, my work has focused on both clinical and FLASH dose rates and their effect on the normal tissue, cognition, neuroinflammation, and the BBB. My graduate work led to numerous publications and is challenging the fundamental principles used in the field to improve .