ESR 5: Model-based Data Analysis of Radio-sensitization by Hyperthermia in Combination with Radiotherapy

PhD research

Host: Prof. Dr. Stephan Scheidegger

Recruiting organisation: Zurich University of Applied Sciences, ZHAW School of Engineering,Technikumstrasse 9, CH-8401 Winterthur

Duration: 36 months

We will address the quantitative understanding of the synergistic and additive (radio-sensitization) effects of heat and radiation. Different effects on the cellular and systemic levels have been investigated. The integration of these biological aspects into treatment planning requires mathematical descriptions for the radio-sensitization of combined application of heat and radiation. Regarding the dynamics of cellular response, it is challenging to extract descriptive models for all treatment conditions directly from experimental in vitro or in vivo data. An adequate model-framework may help to explore a large variety of dynamic conditions (e.g. varying time intervals between application of heat and radiation, varying heating rates, and temperatures). In the first year, the Ph.D. candidate will adapt the existing framework for model-based data analysis for survival- and Comet-data to other assays (e.g. gH2AX) and use existing experimental or preclinical literature data for model calibration. In the second year, the modeling will be extended to protein-related responses such as heat shock proteins (HSP70) and cellular responses which can interact with the immune system. In the third year, a mathematical description for implementation in a treatment planning system should be derived based on the exploration of the developed dynamic models by computer simulations. This project requires very close and strong collaboration with the other ERS, especially ESR 1-4, 11, 12, and 14.

Background

In the last decades, many improvements concerning equipment and treatment planning tools have driven radiation therapy (RT) towards precise application of radiation doses. Remarkable progress has been made regarding geometrical precision. In contrast to these more engineering – related aspects, the biological knowledge seems to lag behind technology development. In radiation therapy, radiobiological research and extended clinical experience and trials resulted in standardized dose prescriptions and fractionation schemes, whereas for hyperthermia (HT), the thermal dose concept still is unclear. Biological treatment planning would require a quantitative framework for estimating or predicting the radio-sensitizing or supportive effects of HT. To compare different RT fractionation schemes, concepts such as Biological Equivalent Dose BED or EQD2 have been developed which assume a linear quadratic (LQ) relationship between the logarithm of survival and radiation dose. Although the model assumptions are questionable (Scheidegger et al., Z. Med. Phys 21(3), 164–173), these concepts may work for small variations of the dose per fraction around 2 Gy and a comparable range of dose rate. Following this idea, Van Leeuwen et al. (Int J Hyperthermia 33(2) 160–169; Int J Hyperthermia 34(1), 30–38) have developed a similar approach by introducing an equivalent dose EQDRT which is comparing a combined hyperthermia – radiation therapy (HT-RT) with RT solely. This approach could be integrated in a treatment planning system but does not describe the dynamics of the response outside the range for calibration. In contrast to this, the Multi-Hit Repair (MHR) Model (Scheidegger et al., CMMM 2013) is a fully dynamic model describing the synergistic effect of heat and radiation. This model is able to describe a large variety of observed radiobiological effects including time gap or time interval and dose rate – effects and could be used to investigate the dynamic processes leading to radio-sensitization by HT. However, a full model calibration is still missing. An important aim of this project is the development of a framework allowing the comparison between the different models and approaches for a large range of dynamic conditions.

Approach 

Previous research demonstrated the remarkable ability of the MHR model to reproduce the cellular response on different levels by correctly describing survival and Comet assay data simultaneously (Weyland et al., CMMM 2020). However, a full calibration of this model will require large amounts of experimental data acquired under different dynamic conditions (dose rates, time gaps between HT and RT etc.) and by different assays.

The translation of data derived by the work package WP3 and WP5 into mathematical relations valid for all dynamic combinations of RT + HT doses will be an important step forward to biological treatment planning. Key processes and dynamic patterns leading to the therapeutic effects observed by ESR1-4 and ESR15 should be identified using dynamic models (Multi-Hit-Repair (MHR), repair-pathway- or even immunological models. Such models will be used for model-based analysis of preclinical thermal enhancement data (WP3). This knowledge directly contributes to clinical treatment strategies or serves as precursor for descriptive models used for treatment planning (WP4) and supports monitoring strategies for HT effects and clinical evaluation in a systems medicine framework (WP5).

Our research team

Your experience

  • Candidates should have a Master’s degree in Physics (preferably in Biophysics or Medical Physics), Bioinformatics, Systems Biology or comparable.
  • Experience with programming (preferably Python)
  • Excellent higher education track record and strong scientific curiosity
  • Fluent spoken and written English skills

In addition, the following experience would be helpful, but not essential:

  • Experience in biostatistics
  • Basic knowledge and experience in radiation biology

We seek a highly motivated scientist who enjoys an interdisciplinary environment and an interdisciplinary project, able to work independently but also as part of a team.

Our offer

This 3-year PhD position is funded by the Marie Skłodowska-Curie actions of the European Union's Horizon 2020 research and innovation program under grant agreement No 955625.  You will be appointed as fulltime PhD for 3 years with ZHAW School of Engineering. The Marie Skłodowska-Curie (MSCA) programme offers a highly competitive and attractive salary and working conditions. The successful candidates will receive a salary in accordance with the MSCA regulations for early stage researchers. Exact salary will be confirmed upon appointment [Living Allowance = €37.320/year (correction factor to be applied per country) + Monthly mobility allowance = €600. An additional monthly allowance of €500 is applicable depending on family situation. In addition to their individual scientific projects, all fellows will benefit from further continuing education, which includes internships and secondments, a variety of training modules as well as transferable skills courses and active participation in workshops and conferences.

Your application

See recruitment procedure. You can apply using the online application form. For more information about the position you can contact Prof. Stephan Scheidegger or Prof. Ruedi Füchslin. (This email address is being protected from spambots. You need JavaScript enabled to view it., +41 58 934 74 63).

ZHAW School of Engineering, Zurich University of Applied Sciences

The ZHAW is one of the leading universities of applied sciences in Switzerland, located in the Greater Zurich Area. Teaching, research, continuing education, consulting and other services are both scientifically based and practice-oriented. Students benefit from an internationally oriented university that places a special focus not only on conveying practical and specialist competencies, but also on developing social and personal skills. About 13’000 students are enrolled in 28 Bachelor’s and 18 Master’s degree programmes, including a double-degree programme with the Washington State University. In addition, two joint PhD programme, one with the University of Venice in Data Science (machine learning, computer vision) and another one with the University of Zurich and Neuchâtel has been established. The ZHAW is tightly linked with the European Centre for Living Technology in Venice. This institution offers strong scientific support in applied statistics, data analysis, computer vision and modelling.