PhD student 1: DNA Damage Responses, Molecular Signatures and Cellular Sensitivity to Protons
Host organisation: Amsterdam University Medical Centers, contact:
p.krawczyk@amc.uva.nl
Using a unique system enabling X-irradiation and real-time imaging of the cellular responses, as well as the new live-cell microscope installed in the beam-line of the particle accelerator at KVI-CART, the student will elucidate the differences between the kinetics of assembly and disassembly of the fluorescently labelled DNA repair protein complexes at DNA breaks induced by X-rays and protons. The live-cell imaging experiments will be complemented by immunofluorescence staining and confocal as well as super-resolution imaging. Combined, the experiments will unravel mechanistic differences in the kinetics of detection and repair of proton- and X-ray induced DNA lesions.
Further, the student will investigate how the proteome of cells, tissues and tumours from pre-clinical models exposed to proton and X-radiation changes in relationship to dose and time and after combination treatments (e.g. hyperthermia). With the help of comprehensive bioinformatic analysis, this will help to establish the molecular signatures of proton responses and generate input for modelling experiments that can help predict optimal treatment protocols in the clinic.
Finally, the student will characterise the sensitivity of a comprehensive set of DNA repair mutants to proton and X-irradiation, with the aim of establishing the relative contribution of the known DNA repair pathways to the repair of proton-induced lesions.
PhD student 2: Organoids and Stem Cell Response to Protons
Host organisation: University Medical Center Groningen, contact:
r.p.coppes@umcg.nl
The response of tissue stem cells will determine the response of normal tissues to proton therapy. We will investigate the biological mechanisms underlying the response of salivary gland stem cells to proton irradiation and the consequences for the tissue regenerative potential. We will use in vitro cultures of salivary gland stem cell derived organoids to study radiation responses to understand proton/particle radiation induced DNA damage responses of stem cells. Post-radiation organoid self-renewal and differentaition potential will be assessed in combination with histological analysis, proteomics, transcriptomics and epigenetics. DDR inhibitors and genetically modified animals will be used to dissect differences in DNA damage responses between X-ray and proton-irradiated organoids. These experiments will yield understanding of DDR in salivary gland (stem cells), and novel proton therapy strategies and informing studies will be performed with the long-term goal of achieving the maximum regenerative potential of normal tissue after radiation treatment for head & neck cancer.
PhD student 3: Proton-Immuno therapy for brain and Glioblastoma
Host organisation: Maastricht University Grow School for Oncology, contact:
marc.vooijs@maastrichtuniversity.nl Web:
www.maastrolab.nl
In this project you will identify, compare and study proteins that are released by tumors after proton- or photon irradiation and how this can be exploited to improve combination treatments of proton therapy and immunotherapy. You will use primary patient-derived tumor and normal cell models as well as in vivo tumor models. The focus in this project is on the most common adult brain tumor Glioblastoma for which there is no cure and immunotherapies have not led to marked improvements yet. In collaboration with the consortium you will also investigate how these treatments affect normal brain (stem cell) function (e.g cognition).
PhD student 4: In vivo imaging of orthotopic tumor models, imaging and interaction with hyperthermia
Host organisation: Erasmus University Medical Center Rotterdam; contacts:
j.essers@erasmusmc.nl or
r.kanaar@erasmusmc.nl
The project aims to define the therapeutic efficacy of proton versus photon irradiation and identify any proton combination treatments for head and neck cancer that are superior to photon irradiation. The project will make use of X-ray CT and fluorescence based molecular tomography yielding complementary information on both anatomy and biological activity of the tumour. Quantitative analysis of these data will be set up to take full advantage of the acquired information and to study spatiotemporal changes with high sensitivity, accuracy, and reproducibility. To this end we will develop novel image analysis techniques for automatic image alignment, detection and segmenation of relevant structures and quantitative measurements of the spatial and temporal properties of these structures.
PhD student 5: Physics and planning of pre-clinical particle therapy research
Host organisation: University of Groningen, KVI-Center for Advanced Radiation Technology; contact:
brandenburg@kvi.nlProject description:
In recent years technology has been developed for image guided X-ray irradiations in preclinical radiation oncology research. With this technology detailed and accurate studies of the radiation response of both tumor and normal tissue have become feasible. The objective of the project is to port this technology to image guided irradiations with protons and other ions in order to facilitate high quality preclinical studies aiming at further optimization of particle therapy, an emerging treatment modality in radiation oncology that since 2018 is available also in the Netherlands. The project encompasses the following aspects:
- Radiation transport and dose calculations in particle irradiations, where we will study the possibilities to improve the quality of fast deterministic radiation transport calculations to the level of the “gold standard” Monte Carlo simulations
- Improvement of the tissue characterization obtained from X-ray imaging by means of proton imaging
- Automated delineation of the anatomical structures that should be irradiated or avoided in order to speed up the image guided irradiation planning.