Our Neuroblastoma Research
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Neuroblastoma is a pediatric cancer of the sympathetic nervous system. It is the most frequent extra-cranial solid childhood tumor, affecting 10-20 children per year in Belgium. These tumors mostly occur in the adrenal glands in the abdomen and the nervous tissue in the neck, chest, abdomen and pelvis.
The currently employed intensive multi-modal therapies still achieve disappointingly low perspective for cure, with less than 50% survival rates. In addition, patients that do survive suffer from serious long-term side-effects, including secondary cancer later in life. As such, there is an urgent medical need for more effective and less toxic therapeutic strategies for high-risk neuroblastoma patients, with the integration of precision oncology biomarkers for patient stratification and therapy prediction and monitoring. |
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Chromosomal copy number alterations as smoking guns for new therapies
Neuroblastoma tumors exhibit a low mutational burden but frequently harbor recurrent focal and large segmental DNA copy number alterations (CNAs) that are strongly associated with poor prognosis. These CNAs serve as critical genomic indicators pinpointing loci that likely harbor oncogenes or tumor suppressor genes essential for neuroblastoma tumor pathogenesis.
Our research strategy exploits these CNAs as molecular “smoking guns” to systematically identify and validate different tumor dependencies through integrative genomic and functional analyses. By elucidating the biological significance of these altered regions, we aim to discover novel therapeutic targets that can be leveraged for the development of precision medicine approaches in neuroblastoma treatment.
Our research strategy exploits these CNAs as molecular “smoking guns” to systematically identify and validate different tumor dependencies through integrative genomic and functional analyses. By elucidating the biological significance of these altered regions, we aim to discover novel therapeutic targets that can be leveraged for the development of precision medicine approaches in neuroblastoma treatment.
Novel combination therapies targeting replication stress resistance and DNA damage repair
Evidence is emerging that cancer cells can adopt a so-called ‘addictive cellular state of replication stress resistance’. Such adaptations can serve as cancer vulnerabilities and potential novel drug targets. While several important chemotherapeutic compounds impose replication stress in cancer cells to toxic levels, more recent small molecule-based approaches are now emerging which target DNA damage response pathways. Our team exploits the therapeutic power of small molecule inhibitors impacting on key vulnerable therapeutic nodes in the replication stress response or DNA damage repair pathways as novel entry points for innovative and effective combination therapeutic regimens.
Targeted protein degradation - PROTAC development
Targeted therapies with small molecules almost invariably cope with the problem of escape mechanisms leading to relapse. Recently, ‘Proteolysis Targeting Chimeras’ (PROTACs) have become a promising and appealing technology for targeted degradation of a protein of interest and opening opportunities for efficient and sustained targeting of onco-proteins through rapid intracellular degradation. These bifunctional molecules recruit a specific E3-ubiquitin ligase (e.g. CRBN, VHL, MDM2) causing proteasome mediated degradation of bound target proteins. While current small molecules act through stoichiometric interactions with their target, PROTACs trigger protein degradation through very short proximity "catch-and-release" (catalytic) interactions. This translates into more potent compounds that only require low systemic concentrations, thereby reducing possible undesired off-target effects.
In addition, PROTACs lead to degradation of the entire protein while most small molecules only block one domain of a proteins, holding the risk for compensatory drug escape mechanisms.
We are closely collaborating with the team of prof. Serge Van Calenbergh of the pharmacy department at Ghent University to develop and validate PROTACs for interesting targets in neuroblastoma.
In addition, PROTACs lead to degradation of the entire protein while most small molecules only block one domain of a proteins, holding the risk for compensatory drug escape mechanisms.
We are closely collaborating with the team of prof. Serge Van Calenbergh of the pharmacy department at Ghent University to develop and validate PROTACs for interesting targets in neuroblastoma.
Single-cell and spatial multi-omics to modulate immune responses
In recent years, significant research across various cancer types has focused on how to manipulate the tumor immune microenvironment (TIME) to enhance immune recognition and destruction of cancer cells. However, applying immunotherapy to neuroblastoma has proven especially challenging, as these tumors are typically classified as immunologically “cold,” with minimal lymphocyte infiltration.
In our lab, we are investigating strategies to 'heat up' the neuroblastoma TIME, making it more receptive to immune cell activity and, ultimately, more responsive to immunotherapy.
These projects are conducted in collaboration with the GOA consortium, where we work closely with several research groups at Ghent University (UGent, CRIG, VIB Ghent) to tackle this complex challenge together.
In our lab, we are investigating strategies to 'heat up' the neuroblastoma TIME, making it more receptive to immune cell activity and, ultimately, more responsive to immunotherapy.
These projects are conducted in collaboration with the GOA consortium, where we work closely with several research groups at Ghent University (UGent, CRIG, VIB Ghent) to tackle this complex challenge together.
