24/07/2019
Marie Skłodowska-Curie Actions
Science 4 Refugees

THERADNET Marie Curie ITN: 9 Early Stage Researcher Fellowships (ESR) – 3 YEAR PHD POSITIONS


  • ORGANISATION/COMPANY
    University of Zurich, Switzerland
  • RESEARCH FIELD
    Medical sciencesMedicine
  • RESEARCHER PROFILE
    First Stage Researcher (R1)
  • APPLICATION DEADLINE
    31/03/2020 17:00 - Europe/Brussels
  • LOCATION
    Multiple locations, see work locations below.
  • TYPE OF CONTRACT
    Temporary
  • JOB STATUS
    Full-time
  • HOURS PER WEEK
    35-42
  • OFFER STARTING DATE
    01/06/2020
  • EU RESEARCH FRAMEWORK PROGRAMME
    H2020 / Marie Skłodowska-Curie Actions
  • REFERENCE NUMBER
    101
  • MARIE CURIE GRANT AGREEMENT NUMBER
    860245

Locations: Multiple Locations

Company/Institute: Institutions across Europe in the THERADNET ITN network

12 positions are available for a 3-year PhD position funded by the Marie-Sklodowska-Curie Innovative Training Network (ITN) "THERADNET”.

The EU-funded Innovative Training Network THERADNET aims to provide a multidisciplinary and intersectorial training to 15 early stage researchers (ESRs) in the field of experimental radiation oncology. THERADNET stands for: "International NETwork for training and innovations in THErapeutic RADiation".

As a consortium of eight leading Radiobiology Laboratories in Europe, THERADNET will bring together radiation biologists, clinician scientists, clinicians and non-academic partners across Europe to investigate the plasticity of an altered tumor metabolism and tumor microenvironment, including the immune system, prior to, and in response to radiotherapy, as well as related dose-limiting adverse effects in normal tissues. The research program covers three scientific work packages addressing tumor sensitization, normal tissue protection and adaptation and escape mechanisms.

Keywords: Radiobiology / Cancer Biology / Cell Biology / Tumor Microenvironment / Tumor Immunology / Tumor metabolism / Medical (radiation-related) Physics / DNA Damage / Preclinical Imaging /

Application

To apply for a specific ESR-position of interest to you, please approach the respective contact person. Please be aware that some positions will open later than others (starting from fall 2019 until spring 2020). ). The application is open until 1-2020, until a suitable candidate is found or will be Extended thereafter. Applicants must fill-out a specific application form and send it to the contact Person of the envisaged ESR project.

Description of the ESRs:

ESR 1: Metabolic control of radioresistance in breast cancer

Host: Université catholique de Louvain

Contact person: pierre.sonveaux@uclouvain.be.

Location: Louvain, Belgium

Breast cancer is the first type of cancer in women worldwide, and Europe has the highest rate of diagnosis. Chemoradiotherapy associated with surgery is part of standard breast cancer clinical care, but tumors can relapse, often because cancer cells acquire intrinsic chemoradioresistance. Our project aims to test the possibility that metabolic alterations are responsible for the acquired radioresistance of breast cancer cells to X-rays. Based on previous observations of our team in head and neck squamous cell carcinoma cells the focus will be set on mitochondria, as these organelles control DNA repair (ATP generation), cell proliferation (biosynthesis) and apoptosis (cytochrome c, superoxide and Ca2+ release). Because it is not protected by histones and has limited repair capacities, mitochondrial DNA (mtDNA) also potentially constitutes a main target of radiotherapy, which will be investigated together with mitochondrial turnover (mitophagy and mitochondrial biogenesis).

This project will identify a metabolic profile associated with radioresistance and lay the ground for antimetabolic strategies aimed to radiosensitize breast cancer cells and, potentially, other cancer types.

 

ESR 2: In vivo real-time imaging of the impact of ionizing radiation on cellular energy metabolism

Host: University of Zurich

Contact person: martin.pruschy@uzh.ch

Location: Zurich, Switzerland

Although radiotherapy is used in more than half of cancer treatments, the effect of ionizing radiation on a differential metabolism in tumor and healthy cells is not well understood. The aim of this project is to collect quantitative data on the energy metabolism of healthy and tumor brain cells using recently developed fluorescent biosensors which allow measuring metabolic parameters in vivo and in real time. This project will be performed in collaboration with Prof. B. Weber at the University of Zurich, who is world-leading expert for in vivo real-time bioimaging. Simultaneously, we will perform millimeter-scaled tumor irradiation to understand the effect of ionizing radiation on the energy metabolism in vivo.

These data will provide fundamental insights to better target the effect of ionizing radiation on the energy metabolism of tumor cells. For the first time, we will provide a real-time readout of ionizing radiation (and anti-tumor drugs) on critical parameters of energy metabolism. This hybrid method coupling ionizing radiation and real time imaging of metabolic substrate is expected to significantly advance the knowledge of tumor biology and therefore provide a knowledge to increase radiotherapy efficiency.

 

ESR 3: THIS POSITION IS NO LONGER AVAILABLE

 

ESR4: THIS POSITION IS NO LONGER AVAILABLE

 

ESR5: THIS POSITION IS NO LONGER AVAILABLE

 

ESR6: Impact of radiation quality (photons versus protons) on molecular and cellular responses

Host: West German Proton Therapy Centre

Contact person: beate.timmermann@uk-essen.de / claere.vonneubeck@uk-essen.de 

Location: Essen, Germany

Proton beam therapy is increasingly applied in cancer treatment, as it promises to reduce normal tissue damage at critical radiosensitive structures. However, some recent reports point to a potential biological effect of the increased LET of protons at the distal edge of the spread out Bragg peak (SOBP) in tumor models and normal tissue damage models in vitro and in vivo. So far, potential differences in the biology of induced DNA damage and the resulting cellular responses between irradiation with photons or protons are not well understood. We propose to use state-of-the art radiobiology endpoints as well as innovative molecular (CRISP/cas9) and cell biology methods (e.g. 2D, 3D culture) and high resolution microscopy to compare the consequences of irradiation with photons and protons at the molecular (DNA damage and repair) and cellular level (survival, signaling) in tumor cells and normal tissue cells and to explore the consequences of genetic or pharmacologic inhibition of molecular factors involved in the regulation or execution of DNA repair.

The proposed project will define similarities and differences in DNA damage induction and repair, cell survival and cell signaling of tumor and normal tissue cells in response to irradiation with photons and protons (plateau, spread out Bragg peak, distal Bragg peak) and elucidate if cells with specific defects in the DNA damage response might be more sensitive or resistant to proton irradiation. These results are of clinical relevance as they may help to select patients that could particularly benefit from proton or photon therapy and to define rational approaches for combining proton therapy with drugs targeting components of the DNA repair machinery.

 

ESR7: Preventing radiation-induced normal tissue toxicity, a role for the immune system?

Host: Universiteit Maastricht

Contact person: ludwig.dubois@maastrichtuniversity.nl

Location: Maastricht, The Netherlands

Lung cancer is by far the most common thoracic malignancy worldwide. Radiation in combination with chemotherapy is currently the standard treatment for locally advanced stages, sometimes in combination with targeted agents or immunotherapy. Treatment however is often associated with high rates of radiation-induced adverse effects. Strategies to reduce the likelihood of radiation-induced tissue damage are through adherence to dose-volume constraints or the use of radioprotectors. Using a dedicated precision image-guided small animal irradiation device, we already have shown the feasibility of longitudinal CT-based monitoring of targeted upper right lung irradiation and the possibility to monitor the effects of anti-fibrotic drugs. The overall objective of this project is to understand the biology of radiosensitivity and how to exploit this for therapeutic gain by investigating what thoracic organ sub-regions are most radiosensitive using dose painting approaches, how polyphenols as caffeic acid phenethyl ester (CAPE) protect these sub-regions by elevating oxidative stress to promote anti-inflammatory and immunomodulatory effects.

This project will provide insights in the differential radiosensitivity of thoracic organ sub-regions in order to identify the areas to be spared as much as possible or the areas that can withstand a higher dose. This will enable future biology-guided radiotherapy as opposed to current clinical practice. Additionally, the protective effects of CAPE and the molecular mechanisms supporting these effects will be elucidated for the different organ sub-regions.

 

ESR8: Targeting pathologic macrophages for widening the therapeutic window

Host: Universitätsklinikum Essen

Contact person: verena.jendrossek@uni-due.de

Location: Essen, Germany

Macrophages play a central role in tissue homeostasis, orchestration and resolution of inflammation, and tissue repair but they also support tumor growth and are suspected to promote resistance to radioimmunotherapy. These pleiotropic actions are based on the pronounced plasticity of the macrophage phenotype that differs depending on tissue/tumor type, microenvironment and treatment. We revealed that radiation-induced environmental changes in normal and tumor tissues induce monocyte/macrophage recruitment, (re)polarization and phenotypic changes towards M2-like pro-fibrotic or pro-tumorigenic phenotypes. However therapy-induced phenotypic changes as well as phenotypic similarities and differences between TAMs and fibrosis-associated macrophages require further definition if we aim to target macrophage responses to improve treatment outcome. Here we aim to define the role of macrophage plasticity (TME-induced, therapy-induced) for both, the efficacy and toxicity of radiotherapy and combined radio-immunotherapy.

Using adequate in vitro co-culture systems and in vivo tumor and normal tissue toxicity models in immunocompetent mice this project will establish spatiotemporal local and systemic changes in the macrophage molecular repertoire during the course of radiation treatment (blood, tumor, normal tissue), their impact on other immune cell types, and potential radiation-induced environmental changes driving phenotypic immune changes in tumor and normal tissues. This research will reveal response-markers and therapeutic targets for improving efficacy of radio(immuno)therapy without increasing toxicity by targeting macrophage-induced therapy escape.

 

ESR9: Radiotherapy treatment volume and tumor immune response

Host: University of Zurich

Contact person: martin.pruschy@uzh.ch

Location: Zurich, Switzerland

Preclinical studies with hypofractionated regimens have revealed that increased doses of ionizing radiation (IR) induce potent anti-tumor immune responses, as a result of IR-induced immunogenic tumor cell death. These insights have boosted an immense level of translational and clinical research at the interface of radiotherapy and immunology leading to promising clinical trials of radiotherapy in combination with immune checkpoint inhibitors. However, we have only limited insight on such fundamental questions how radiotherapy with larger treatment volumes will affect the immune system and subsequently the tumor immune response. Here we will investigate the impact of the radiotherapy treatment volume on the efficacy and the immune response alone and in combination with immune checkpoint inhibitors against the irradiated primary tumor and abscopal tumor burdens.

This project will, using adequate preclinical murine tumor models and a state-of-the art small animal image-guided radiotherapy platform, establish a relationship between the size of the radiotherapy treatment volume directed against the primary tumor, the immunological responses and the therapeutic outcome towards the primary but also the non-irradiated secondary tumor. This research project will therefore contribute to a better understanding and potential treatment optimization of patients in this scenario.

 

ESR 10: THIS POSITION IS NO LONGER AVAILABLE

 

ESR11: Targeting metabolic cancer cell plasticity to overcome escape from radiotherapy

Host: Universitätsklinikum Essen.

Contact person: verena.jendrossek@uni-due.de / Johann.Matschke@uk-essen.de

Location: Essen, Germany

Hypoxia is a common feature of human solid tumors and is considered as one main biological factor promoting tumor cell resistance to radiotherapy. Others and we revealed that chronic intermittent hypoxia acts as an important driver of adaptive changes that allow the cancer cells to survive these highly adverse conditions and promote tumor heterogeneity. A hypoxia/reoxygenation-induced metabolic reprogramming allowed the cancer cells to meet their bioenergetic and metabolic demands for sustained proliferation and survival after exposure to ionizing radiation. But the contribution of the genetic background to the metabolic response to radiotherapy and of the tumor cell intrinsic or induced metabolic plasticity to the escape of the cancer cells from radiotherapy remain to be defined.

The proposed project will profile metabolic demands of cancer cells with distinct genetic backgrounds upon exposure to ionizing radiation under diverse environmental conditions. Novel therapeutic strategies for overcoming intrinsic and acquired mechanisms for metabolic escape from radiotherapy will be defined and marker constellations for individualization of cancer radiotherapy will be predicted and validated in vitro and in vivo.

 

ESR12: Metabolic control of metastases in irradiated breast cancer

Host: Université catholique de Louvain

Contact person: pierre.sonveaux@uclouvain.be.

Location: Louvain, Belgium

Defects of mitochondrial function have long been suspected to contribute to the development and progression of cancer. Mitochondria besides their roles as powerhouses and biosynthetic hubs are a main source of ROS. Indeed, the maintenance of the mitochondrial potential by means of electron transfer chain (ETC) during respiration produces superoxide as a main byproduct. In cancer cells, it has been reported that natural occurrence of mutations partially impairing ETC complex I and identification of an unprecedented phenotype corresponding to TCA cycle overload promote mtROS-dependent tumor metastasis. In this context, we recently found that several chemotherapies, including doxorubicin and cisplatin, promote ROS production and ROS-induced breast cancer cell migration and metastasis. On the other hand, in another tumor type, we also found that radiotherapy increases cancer cell respiration and promotes a morphological change evoking an epithelial-to-mesenchymal transition (EMT). Here, we will thus investigate whether X-ray radiotherapy promote breast cancer cell EMT, migration, invasion and metastasis.

This project will increase the understanding how radiotherapy promotes the metastatic potential of cancer cells and how mitochondria-targeted anti-oxidants or other metabolic targets might reverse this phenotype.

 

ESR13: THIS POSITION IS NO LONGER AVAILABLE

 

ESR14: THIS POSITION IS NO LONGER AVAILABLE

 

ESR15: Interaction between theranostics and external beam radiotherapy

Host: University of Oxford

Contact person: Katherine Vallis

Location: Oxford, United Kingdom

FOR THIS POSITION, YOU HAVE TO APPLY DIRECTLY HERE

Subcellular Targeting of Radiosensitizers and Radionuclides to Enhance Radiotherapy

The capacity of pharmaceutical agents to selectively find their biological targets is an important determinant of their usefulness in clinical medicine. Many pharmaceutics are directed against intracellular targets that reside in organelles. Carriers that selectively target these subcellular structures have been investigated, and include nanoparticulate drug carriers, chemically modified proteins and deoxyribonucleotide-based agents. As well as the nucleus, the mitochondria, endoplasmic reticulum, Golgi-complex, the lysosomal system have all been investigated as intracellular targets of irradiation. There is increasing evidence that the nucleolus, the site of ribosomal assembly, plays an important role in sensing and orchestrating the response to cellular stresses including that which occurs in response to radiation. Therapeutic strategies that specifically hamper nucleolar function are being investigated in cancer and may be particularly effective in combination with radiotherapy. The initial central aim of this project will be to develop nucleolar-targeting oligonucleotide-based agents aimed at causing nucleolar functional disruption and radiosensitisation. Direct delivery of radiation to nucleolar sites using oligonucleotide-based radionuclide-labelled compounds will also be tested.

 

Specific methods:

DNA repair signalling analyses

Oligonucleotide design and synthesis

Radiolabelling

Immunohistochemistry and immunofluorescence

Colony formation assays.

 

Relevant previous publications

Jackson M et al., Cancer Res. 79:4627-37, 2019.

Bavelaar B et al., Front Pharmacol. 9:996, 2018.

Thomas E et al., Theranostics, 9: 5595-609, 2019.

Gill MR, Vallis KA. Chem Soc Rev. 48:540-557, 2019.

Cornelissen B et al., EJNMMI Res. 2:9, 2012

 

Benefits

- You will be employed by the host organisation for 36 months. Extended duration of a PhD-project will be individually handled

- You will benefit from the designed training programme offered by the host organisation and the consortium.

- You will participate in international secondments to other organisations within the THERADNETnetwork and in outreach

activities targeted at a wide audience.

- You will embark on secondments to THERADNET partners for trans- and interdisciplinary research.

- You will be part of an international research consortium of over > 25 Researchers

- You will get in contact with the other members of this international consortium and will benefit from the joint

training platform to develop skills in the area of applied radiation biology, translational oncology research and personalized Medicine.

Eligibility criteria

- Applicants must fulfill the “H2020 MSCA Mobility Rule” and the “H2020 MSCA eligibility criteria”

- Applicants can be of any nationality.

- Applicants must be eligible to enrol on a PhD programme at the host institution (or at a designated university in case

the host institution is a non-academic organisation).

- Applicants must have an ability to understand and express themselves in both written and spoken English to a level that is

sufficiently high for them to derive the full benefit from the network training.

 

Offer Requirements

  • REQUIRED EDUCATION LEVEL
    Medical sciences: Master Degree or equivalent
  • REQUIRED LANGUAGES
    ENGLISH: Good

Skills/Qualifications

  1. Early Stage Researchers: "Early Stage Researchers (ESRs) must, at the date of recruitment by the host organization, be in the first four years (full-time equivalent research experience) of their research careers and have not been awarded a doctoral degree. Full-Time Equivalent Research Experience is measured from the date when the researcher obtained the degree entitling him/her to embark on a doctorate (either in the country in which the degree was obtained or in the country in which the researcher is recruited, even if a doctorate was never started or envisaged)."

  2. H2020 MSCA Mobility Rule”: researchers must not have resided or carried out their main activity (work, studies, etc.) in the country of the host organisation for more than 12 months in the 3 years immediately before the recruitment date. Compulsory national service, short stays such as holidays, and time spent as part of a procedure for obtaining refugee status are not taken into account."

  3. Applicants can be of any nationality and must be eligible to enroll on a PhD Programme at the host institution

  4. Applicants must have an ability to understand and express themselves in both written and spoken English to a level that is sufficiently high for them to derive the full benefit from the network training

Specific Requirements

We are looking for highly motivated candidates who recently obtained a Master degree in life sciences and have been working in the area of cell biology, molecular biology, tumor biology and/or radiobiology.

 

Map Information

Work location(s)
2 position(s) available at
University of Zurich
Switzerland
ZH
Zurich
8057
Wintherthurerstr. 190
2 position(s) available at
Université Catholique de Louvain
Belgium
Louvain
2 position(s) available at
University of Oxford
United Kingdom
Oxford
2 position(s) available at
Universiteit Maastricht
Netherlands
Maastricht
1 position(s) available at
West German Proton Therapy Centre
Germany
Essen
2 position(s) available at
Universitätsklinikum Essen
Germany
Essen
2 position(s) available at
Institut Curie Paris
France
Paris
2 position(s) available at
Technische Universität Dresden
Germany
Dresden

EURAXESS offer ID: 430939

Disclaimer:

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