Author ORCID Identifier
0000-0002-3031-1921
Date of Graduation
8-2021
Document Type
Dissertation (PhD)
Program Affiliation
Medical Physics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Gabriel Sawakuchi
Committee Member
Sang Cho
Committee Member
David Grosshans
Committee Member
Radhe Mohan
Committee Member
Asaithamby Aroumougame
Committee Member
Simona Shaitelman
Committee Member
Jason Stafford
Abstract
Radiation therapy with ions has a number of advantages over conventional radiation therapy with photons, including favorable depth-dose distributions, greater relative biological effectiveness (RBE) and a lesser dependence on a number of biological factors known to affect radiosensitivity to photons, including DNA repair capacity. Thus, it is expected that an additional benefit of using ions is that they mitigate the great heterogeneities in treatment responses commonly observed in photon therapies.
However, by analyzing the cell survival of human cancer cell lines exposed to clinically relevant photon, proton, and carbon ion beams, we show there is not significantly less relative variability in intrinsic radiosensitivity between radiation qualities. These data imply that predicting intrinsic radiosensitivity – for which some research is underway for photon therapies – can provide similar benefits in the case of ion therapies in helping to mitigate heterogeneities in treatment response.
We also showed that there is no less variability in radiosensitivity between radiation qualities if the cells’ DNA repair pathways are inhibited pharmacologically, which implies that DNA repair capacity remains relevant to determining intrinsic radiosensitivity, even for ions. We confirmed this fact by characterizing the survival of cell lines with differential DNA repair capacity exposed to photons, protons, helium and carbon ions, and by quantifying DNA repair by imaging immunohistochemically stained DNA repair proteins. We also showed that while non-homologous end joining repair is the more important DNA repair pathway, its importance relative to homologous recombination repair decreases with increasing ion linear energy transfer.
Finally, we created an empirical model to predict cellular radiosensitivity to ions on the basis of that cell’s radiosensitivity to photons, and showed that this model can predict the response of cells with differing DNA repair capacity, whether naturally occurring, or induced by gene modification of pharmacological inhibition.
This work may be directly useful in the context of novel radiation therapies combined with DNA repair inhibition, as our work suggests that similar relative sensitization to ions as to photons can be achieved through DNA repair inhibition, and we present a model that can be used to predict ion radiosensitivity or RBEs in spite of this modulation.
Keywords
RBE, radiation therapy, protons, carbon ions, radiation biology, DNA repair, intrinsic radiosensitivity, biological modeling