The project

High-grade gliomas (HGG) in adults and children, such as glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) are highly fatal tumors for which in recent decades no significant breakthroughs in therapy have been accomplished. Most patients die within the first year after diagnosis.

For most patients with locally advanced solid tumors outside the brain after surgery, the combination of chemotherapy and radiotherapy, e.g. ‘ chemo-radiotherapy’ has become the standard modality, leading to better local tumor control and prolonged survival rates. The fundamental problem of limited drug permeability of the blood-brain-barrier (BBB) has so far limited/hampered the translation of this concept into viable therapeutic paradigms for HGG, in particular for WHO grade IV, adult GBM and childhood DIPG.

Due to the diffuse nature of the disease, invading vital areas of the brain, radical surgery per definition is not an option for affected patients. Chemotherapy has displayed limited efficacy, partly due to a low BBB-permeability. As a consequence, radiotherapy has generally remained as the only viable therapeutic option after surgery. Unfortunately, the low radiosensitivity of high grade glioma has limited radiotherapy to a largely palliative role, which has not improved the long-term prognosis of affected patients. It is in this context particularly noteworthy, that there is growing evidence from gene expression profiling that the observed radio-resistance for HGG is associated with upregulation of genes involved in DNA repair, such as PARP1, which is a protein directly involved in single strand DNA-break repair and thus plays an important role in radiation resistance.

Recent advances in the field of microbubble-mediated focused ultrasound induced BBB disruption (BBBD) have opened new possibilities to deliver chemotherapeutic agents across the BBB. This mechanism increases both transcellular transport and paracellular passage of chemotherapeutic agents such as doxorubicin of a factor of up to twenty-fold for durations of up to four hours, with a return to full BBB impermeability shortly after therapy. Since the process has shown to be reversible and is not hampered by severe side-effects, this potentially provides a mechanism of repetitive, precise local drug-delivery to malignancies, in which generally the permeability of the BBB is not significantly altered, such as non-enhancing parts of adult GBM and DIPG.

This preclinical research project aims to translate this innovative drug delivery technology – focused ultrasound (FUS) mediated BBBD - to preclinical models of DIPG and pHGG. We will use the technique in vivo, in combination with radiotherapy, to deliver drugs that we previously found to be associated with potent radiosensitization in HGG cells in vitro, such as inhibitors of PARP1, HDAC or Wee1. The goal is to overcome the radiation resistance of HGG, leading to better tumor control and increased survival, and, as such be an important step towards a more effective treatment for DIPG and pHGG patients.

Therefore, the translational aim of this project is to bring the technological innovation of sonoporation into the field of radiation-/neuro-oncology to set the basis for sonoporation- enhanced radio-chemotherapy in DIPG and pHGG patients. You will investigate FUS radiochemotherapy in vivo, in orthotopic, patient-derived DIPG and pHGG xenograft models.

Tasks and responsibilities

You will be responsible for the preparation, execution, and analysis of animal experiments (Article 9 of the Experiments on Animals Act Certification prefered) and will work in close collaboration with physicians, postdocs and other PhD students within the Princess Maxima Center for Pediatric Oncology, Amsterdam UMC (location VUmc), as well as at the UMC Utrecht Center for Image Sciences. You will remain up to date with respect to new developments in the field and will publish and present your own research in peer-reviewed journals and at national and/or international conferences.

We are looking for an enthusiastic and highly motivated researcher with:

• A MSc degree in biomedical engineering, biomedical sciences, pharmacology, medicine, medical biology, biochemistry or a related field;
• A natural level of scientific thinking, a can-do mentality, a strong drive for a career in science, an
• inquisitive, creative mind, and who are curious and eager to learn;
• You are required to be certified for conducting animal experiments ('artikel 9') and have affinity with working with animals;
• Willing to work with patient models based on xenograft transplantations and at a radionucleotide lab, although not per se with radioactive material;
• You will work on a variety of aspects of this project requiring knowledge of pharmacology, drugs, physics (ultrasound), biomedical engineering, tumor-related proteins, and brain anatomy and pathology;
• Although a level of independence is expected, you should be motivated to work in a multidisciplinary team and should show a teamwork mindset’;
• You are certified to work at a radionucleotide lab have an advantage, although this course can be taken at the start of the PhD as well.

We offer a challenging PhD project in a social and ambitious research group. The total duration of the project is 4 years (full-time). You will initially be appointed for a period of one year, after which your performance is evaluated and your contract may be extended with three years. The project will take place at the UMC Utrecht, as well as Amsterdam UMC, location VUmc.

The gross salary is €2665 per month (scale 45-6, collective labour agreement ‘Ziekenhuizen'), supplemented with 8,33% holiday allowance and an 8.33% year-end bonus.

Princess Máxima Center for Pediatric Oncology

The Princess Máxima Center for Pediatric Oncology is a new nationwide research hospital concentrating healthcare, research and education with regard to cancer in children and is located in Utrecht, de Uithof. The institute has the ambition to give the best treatment to children with cancer with the highest cure rate and the least side effects of (often complex) anti-cancer treatment. The center brings together the best possible care and scientific research, creating a

unique interdisciplinary institute for pediatric oncology in Europe.

DIPG and high-grade glioma are largely fatal brain tumors in children and adults that need innovation in treatment. This highly innovative preclinical research project explores the use of sound waves for better drug delivery to the brain, to improve response to radiotherapy