PhD Thesis Proposal: Jacob Sunnerberg

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Meeting ID: 216 428 8762

"Mechanistic Insights into the FLASH Effect: The role of oxygen and radiation chemistry in ultra-high dose rate radiation therapy"

Abstract

The development of new cancer therapies focuses on widening the therapeutic window between tumor control and normal tissue toxicity. Over the past decade, research into ultra-high dose rates (UHDR) for radiation therapy, known as FLASH-RT, has gained momentum due to its ability to reduce normal tissue damage while maintaining tumor control compared to conventional dose rates. However, a major challenge in the clinical translation of FLASH-RT is the unknown mechanism behind this tissue sparing.

The first aim of this thesis is to investigate changes in the concentrations of chemical species, specifically hydrogen peroxide and molecular oxygen, in protein-rich solutions following radiation delivery across a range of dose rates—from conventional to UHDR—and various oxygen levels. This research is a preliminary step toward understanding how UHDR modifies radiation chemistry relevant to DNA damage pathways in a biologically relevant medium compared to conventional dose rates.

The second aim is to translate these in vitro findings into in vivo murine models, as the FLASH effect is an in vivo phenomenon. Microenvironmental conditions significantly influence the chemical changes induced by UHDR, and biological systems have mechanisms and dynamics that cannot be fully replicated in vitro. Thus, it is essential to evaluate radiation-induced oxygen consumption in vivo to better understand its implications for the FLASH effect. This aim will focus on non-survival experiments measuring oxygen consumption under various beam parameters and tissue oxygenation levels in murine flank skin.

The third and final aim is to assess the utility of in vivo oxygen consumption as a predictive metric for the FLASH effect. This will involve skin toxicity studies where oxygen consumption is measured during radiation delivery and correlated with the time to lesion development in mouse flank skin across a range of tissue oxygen levels for both conventional and UHDR delivery. While dose rate dependence on oxygen consumption has been observed in vivo, it is unclear whether this transient change in local oxygen significantly impacts tissue response. This work aims to elucidate the role of oxygen consumption in the FLASH sparing of healthy tissue.

Thesis Committee

• Brian Pogue (Chair)
• David Gladstone
• Petr Bruza
• Jack Hoopes
• Jennifer Wei Zou (UPenn)

Contact

For more information, contact Thayer Registrar at thayer.registrar@dartmouth.edu.