Pediatric high-grade gliomas are aggressive tumors with a dismal prognosis, and poor patient progression-free and overall survival, e.g., a median survival of 11 months in patients suffering from diffuse intrinsic pontine glioma. Of the therapeutic challenges of clinical translation in such malignancies, limited drug delivery, mainly due to the presence of the blood-brain barrier, renders these cancer types insufficiently sensitive to standard-of-care anticancer drug therapies and their combination, thus leading to inevitable recurrences.
One of the most promising non-invasive techniques to induce reversible-blood-brain barrier disruption (BBBD) to date is the use of therapeutic ultrasound, which can be transmitted through the skull to interact with intravascular ultrasound-contrast agents, i.e., microbubbles. This method allows a spatially selective, transient opening for transcellular and paracellular transport pathways. The resulting microbubble-mediated ultrasound-induced BBBD, so-called focused-ultrasound BBBD (FUS-BBBD), is temporary, and does not cause undesired or permanent tissue damage to the central nervous system. First clinical studies with transient FUS-BBBD have shown encouraging results with respect to the achievable pharmacodistribution and absence of side-effects, indicating the potential to significantly expand the possibilities of pharmacological therapies in the brain, in particular for neuro-oncological diseases.
In the Princess Maxima Center for Pediatric Oncology the candidate will join the taskforce of the van Vuurden group to design and validate novel FUS-BBBD enhanced pediatric brain tumor therapies, with a focus on the execution of small-animal in vivo experiments in a clinically-translatable workflow. Of the 150 hours of in vivo technical experience to complete, the following procedures will allow addressing the scientific questions:
- Tumor implantation and monitoring of tumor growth using bioluminescence imaging (BLI)
- FUS-BBBD mediated drug delivery and assessment of tumor response: to do so, the candidate will need to a) catheterize the tail vein, b) apply stereotactic neuronavigation using a BLI camera, and c) perform FUS exposure in a specific brain region of the rodent
- Basic animal handling: animal monitoring, positioning, and injections (subcutaneous, IV)
The candidate will develop his/her skills in histology and state-of-the-art microscopy to evaluate the effect of ultrasound waves and tumor burden (H&E staining of paraffin-embedded tissues, BBB staining), but will also be involved in in vitro drug studies including patient-derived cells.