Thesis

New Radiobiological and Nanodosimetric Insights into Proton Therapy

• Call:

  ProtoTera Call 2020

• Academic Year:

  2020/2021

• Supervisor:

  Ana Belchior

• Co-Supervisor:

  Reinhard Schulte

• Host Institution:

  C2TN - Centro de Ciências e Tecnologias Nucleares

• Granting Degree Institution:

  Instituto Superior Técnico (Universidade de Lisboa)

• Typology:

  Mixed

• Abroad Institution:

  Instituto Superior Técnico (Universidade de Lisboa)

• Abroad Supervisor:

  Octávia Monteiro Gil

• Abstract:

  Unexpected late effects of proton therapy (PT) have been observed over the last few years as the number of patients treated with PT has increased. These side effects could be related to the uncertainties in the increased relative biological effectiveness (RBE) of protons stopping in organs at risk (OAR). RBE values across the spread-out Bragg peak (SOBP) of protons can generally vary from 0.9 – 1.7 [1]. The use of a constant RBE value of 1.1, which is still the accepted clinical practice, disregards experimental evidence that the RBE depends on many factors, including: i) dose per fraction (higher for smaller dose fractions), ii) tissue type (higher for late-response tissue, in particular in the brain), iii) LET/energy (increasing up to a maximum around 50-70 keV/μm, then falling) and iv) biological endpoint (higher for late-response endpoints, including brainstem necrosis and blindness). DNA damage generated by particle tracks with higher LET is thought to be more complex and more difficult to repair. This effect will increase the magnitude of RBE in critical healthy tissues when protons are stopped in them. Moreover, the effect of fractionation is not included in current RBE considerations but certainly plays a role. There is evidence that RBE is higher with fractionation, further amplifying the high-LET effect of stopping protons. The main goal of the thesis is to go beyond the state-of-the-art approach and replace the use of a constant RBE value of 1.1, which disregards experimental evidence that the RBE depends on many factors (described above) with a novel, nanodosimetry-based approach. To achieve this, we propose to systematically study the frequency of larger ionisation clusters in small target volumes of DNA size experimentally with low-pressure gas-based nanodosimetry and with Monte Carlo track structure simulations (Geant4-DNA, or TOPAS-nBio) and correlate them with radiobiological studies. Accordingly, this proposal encompasses a stepwise multidisciplinary approach combining the following scientific objectives: i) Perform Monte Carlo simulation of particle track characteristics to establish nanodosimetric ionisation detail parameters for clinical proton beams at different energies used in the Northwestern Medicine Chicago Proton Center. ii) Perform radiobiological experiments with human cells and establish nanodosimetric parameters that best correlate with the radiobiological results iii) Using the best correlating nanodosimetric parameter(s) create a treatment plan with uniform ionisation detail for a human head phantom with a matrix of embedded cells and demonstrate that a uniform biological effect is observed. For the planned experiments, we will utilise a modern proton therapy centre (Northwestern Medicine Chicago Proton Center in Warrenville, Illinois, USA). The project investigators will jointly direct the research at C2TN and LLU. They will meet weekly on Zoom. The LLU supervisor (Professor Reinhard Schulte) is a leading expert in nanodosimetry. The supervisors at C2TN (Ana Belchior and Octávia Monteiro Gil) feature robust and mature expertise in radiobiology, biological dosimetry, and cytogenetics, as well as a sustained level of international collaborations. Over the years, they have participated in projects and networks of excellence and have published in the scientific domains of relevance. The balance and synergies between the supervisors' expertise will be an added value to attain the proposal's objectives. Access to state-of-the-art irradiation facilities, laboratories, and equipment will be available at the institutions mentioned above.