Kinetics of DNA-repair mechanisms under radiation injury
Conor McFadden, David Flint and Gabriel O. Sawakuchi
From a physics standpoint, technological advances that improve radiation dose delivery to tumor tissue while sparing healthy tissue are reaching their theoretical limit. The physics of radiation interaction with matter is well established for the range of energies used in radiotherapy. Thus, advances in radiation oncology must arise from understanding the biochemical mechanisms involved in detection and repair of radiation-induced cellular damage. However, the biochemical processes involved in DNA repair after radiation-induced damage are not clear, particularly those occurring immediately after irradiation (i.e., within 1 second). Moreover, a lack of experimental techniques capable of precisely measuring radiation in subcellular compartments has hampered radiation biology experiments investigating mechanisms of cell death, pathways of cell repair, and mutation induction for different types of radiation. In this project, we seek not only to develop novel experimental methods to precisely measure radiation in subcellular comportments, but also to study the spatiotemporal behavior of DNA repair proteins within 1 second after radiation-induced DNA injury and to elucidate the DNA repair machinery. This study is expected to create techniques that will allow precise analysis of the effectiveness of different types of radiation in killing different types of cancer cells and enable spatiotemporal measurements of biochemical processes occurring immediately after radiation-induced injury in live cells. This research is expected to provide fundamental understanding of DNA damage response mechanisms in cancer cells. Understanding the biochemical mechanisms activated immediately after DNA damage will guide the development of new pharmacologic strategies to enhance the effects of radiation on cancer cells, possibly leading to improvements in cancer radiation treatments and patient outcomes.
Linear energy transfer (LET) measurements in therapeutic proton beams
Dal Granville and Gabriel O. Sawakuchi
Measurements of LET distributions in proton therapy beams are important to verify, as part of the patient specific quality assurance (QA) measurements, that calculated LET distributions in proton therapy treatment plans are within accepted tolerance levels. Although determination and verification of LET in proton therapy are becoming increasingly important, no practical technique exists for independent verification of LET distributions in proton therapy treatment plans (obtained for example by Monte Carlo or analytical models) on a routine basis. This research aims to provide a new experimental method using optically stimulated luminescence detectors (OSLDs) to perform this independent verification of LET distributions. Because LET is related to biological dose, measurement of LET as a function of depth will provide information on the proton beam’s “biological” range. This information will be useful to improve the efficacy of proton therapy by minimizing distal margins associated with range uncertainties, which in turn will reduce the volume of irradiated normal tissue.
This research is significant because it will improve our ability to measure and verify LET distributions (or validate LET calculations) and correlate them with clinical outcomes for patients treated with proton beams, helping to utilize the full potential of proton therapy and assess its effectiveness. Determination and verification of LET in proton therapy is increasingly important due to: (a) the possibility of using LET distributions as an additional optimization parameter in intensity modulated proton therapy (IMPT); (b) the need to understand the role of LET distribution on treatment outcomes so as to better assess the effectiveness of proton therapy over other radiotherapy modalities. By understanding and controlling LET distributions of therapeutic proton beams it may be possible to create treatment plans with higher LET in the tumor volume and lower LET in healthy tissue, which would maximize tumor control while minimizing complications. Such approach would be important to selectively boost the biological effective dose (BED) of target sub-volumes having relatively lower radiation sensitivities (due to hypoxia and other tumor micro-environmental effects, as determined from molecular and functional imaging studies).
Ionization chamber measurements in the presence of magnetic fields
Daniel J. O'Brien and Gabriel O. Sawakuchi
Implementation and safe use of MRI-linac units will only be possible with the development of methods that can provide accurate dosimetric calibration and quality assurance (QA) measurements of the MRI-linac unit. Because ionization chambers (ICs) have been used as the gold standard for calibration and QA measurements of conventional radiotherapy units, it would be ideal to use these detectors and similar procedures to also perform calibration and QA measurements of MRI-linac units. This research aims to use Monte Carlo simulations to determine correction factors for the use of ICs in the presence of B-fields. This will make possible the implementation and safe use of new MRI-linac units. Of particular importance, this project will generate essential data and methods for MRI-linac dosimetry with ICs.
UT MD Anderson Cancer Center
Department of Radiation Physics
1515 Holcombe Blvd, Unit 94