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The INTO-PROT project
INTO-PROT is a 4-year collaborative research project aiming at further increasing therapeutic window of proton therapy of cancer funded by a Dutch Cancer Society Consortium grant.
Proton/particle therapy is currently mainly used to prevent radiation-induced side effects. However, to achieve the full exploitation of the advantages of proton therapy knowledge on biological mechanisms of tumor and normal tissue response are urgently needed.
The project will investigate and develop future options for proton therapy, focussing on brain and head and neck tumours and normal tissue, covering about 30% of all PT indications. We will study which mechanisms underlie the different damage responses to photon and proton radiation in tumour and normal tissue by studying: DNA repair kinetics, molecular signatures, (stem) cellular sensitivity, biomarkers of immune response and tissue response to protons at different linear energy transfer. Furthermore, the added value of combining proton/particle therapy with response modulators will be studied, including DNA repair modifiers, hypoxia activated drugs, immunotherapy as well as hyperthermia. Better understanding of the mechanisms of damage will allow optimisation of proton therapy combined with the use of novel and existing combination therapies with the intention is to improve tumour control without additional risk of unwanted side-effects, and hence further improving survival and/or quality of life for cancer patients.

INTO-PROT is a consortium formed by investigators from eight leading Dutch research institutes: University Medical Center Groningen (UMCG), University of Groningen (RUG), Maastricht University Medical Center+ (MUMC+), Amsterdam University Medical Center (AUMC), Erasmus University Medical Center Rotterdam (Erasmus MC), KVI-Center for Advanced Radiation Technology (KVI-CART), Leiden University Medical Center (LUMC) and Delft University of Technology (TU Delft). INTO-PROT will operate in association with to institutes liaised to the 3 Dutch Proton Therapy Centers, being the Groningen Proton Therapy Center, Holland Particle Therapy Center, Delft and Zuid-Oost Nederland Protonen Therapie Centrum, Maastricht.

The Consortium is looking for five ambitious PhD-students ready to start their research projects by June 2019.

The project consists of 3 workpackages:
WORKPACKAGE 1: Elucidating the mechanisms of molecular, cellular and tissue response to proton therapy
In WP1 the mechanisms of the response of normal tissue and tumour cells, organoids and tissues to proton therapy will be investigated for molecular signatures of the DNA Damage, cellular, immunological and tissue stem cells induce regenerative responses.

WORKPACKAGE 2: Improving the therapeutic index for proton therapy with combination treatments
WP2 aims to study the effects of various combined therapies to enhance tumour response and ameliorate normal tissue damage, with the aim of increasing the therapeutic window.

WORKPACKAGE 3: Dose delivery, optimisation and planning
WP3 aims to develop and esthablish future more sophisticated optimal proton/particle dose delivery with various beam characteristics, as well as treatment planning, to allow future more sophisticated studies.

Within the INTO-PROT consortium, 5 PhD students will be selected for a 4-year advanced multidisciplinary and intersectoral research training in one or more of the above descibed workpackages.

Job description

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.nl

Project 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.

What do we need

  • You have a Master’s degree or equivalent in M.Sc. degree in Biomedical Sciences, Molecular Life Sciences, Biochemistry, or a related field for wp1-4.
  • For wp5 we ask and M.Sc. degree or equivalent in physics; applied physics; medical physics; biomedical technology or a related field, with basic knowledge of programming (C++, Python), expertise in radiation physics; radiation transport; Monte Carlo and medical imaging techniques and experience in performing experiments at accelerator facilities are an asset.
  • Your educational background matches the requirements of the PhD positions you are interested in.
  • Your are willing to be exchanged for extended periods to one or more of the other participating institutes
  • Licenses to work with animals (Felasa B) and with radiation (level 5b protection) are highly recommended
  • You are an excellent team player, thorough in documentation, clear in communication.
  • You have good English language skills.

What do we offer

  • The PhD student will be appointed at and conform the conditions of the host organisation indicated for each position. We offer:
  • A stimulating and creative learning environment and an interdisciplinary and international research training programme.
  • You will be engaged in transdisciplinary experiences with targeted secondments to practice communities and companies.
  • The full-time (1.0 FTE) PhD position is offered for four years, with a yearly evaluation. Your salary will be € 2.357, - gross per month in the first year and up to € 3.020,- gross per month in the fourth year, according to the PhD candidate salary scale.
  • On top of this, there is an 8% supplementary holiday and an 8.3% year-end bonus per year. Candidates who would need to relocate may be eligible for compensation.
  • Employees relocating from abroad may be eligible for the Dutch ‘30% ruling’, a tax advantage which results in a significantly higher net salary.
  • Conditions of employment are according to the Collective Labour Agreement for Dutch Inviversities (CAO-NU).
  • Assistance in obtaining housing is possible (UM).
  • For UM, local provisions also apply. For more information, see http://www.maastrichtuniversity.nl > Support > UM employees

The UMCG has a preventive Hepatitis B policy. The UMCG can provide you with the vaccination, should it be required for your position.
In case of specific professions a ‘Certificate of Good Conduct’ is required.

Additional information
For more information about a specific position, please contact the person indicated for that position.

For general questions, please do not hesitate to contact the project leader at r.p.coppes@umcg.nl

(please do not use e-mail addresses for applications)

Applying for a job
Please use the digital application at this site - only these will be processed.
You can apply until 14 May 2019.