Description of Research Expertise

The De Raedt Lab focuses on elucidating the mechanisms by which pediatric High Grade Gliomas develop and progress. We aim to understand which pathways are crucial in these processes, how they interact with each other, and how we can exploit these insights to develop novel, paradigm-shifting therapies. To gain insight into what drives these pediatric High Grade Gliomas, we molecularly analyze human tumor samples, perform in depth cellular studies and develop accurate mouse models. Additionally, whenever possible we perform high quality pre-clinical studies in our animal models that, if successful, can be quickly translated to the clinic. Importantly, our work has inspired multiple clinical trials that are currently ongoing.

Pediatric High Grade Glioma (pHGG) is a devastating disease with a median survival of ~12 months. Human hemispheric pHGG are often driven by an aberrantly activated RAS-pathway, for example by loss of NF1. Therefore, a major interest of ours lies in the RAS pathway, one of the major oncogenic signaling pathways in cancer, plays a crucial role in the development of these gliomas. Intriguingly, in pediatric High Grade Glioma, mutations in the epigenetic machinery often co-occur with RAS pathway mutations. Our goal is not only to study and understand the RAS pathway itself (3), but also to use advanced in vivo models and tools to functionally identify and understand how epigenetic mutations cooperate with RAS pathway activation (1). Additionally, we have a keen interest in developing novel therapeutic approaches, including immunotherapy (2).
(1) Functional validation and identification of new (epigenetic) drivers: developing mouse models that are genetically faithful to human central nervous system tumors.
In the current era of next generation sequencing, identifying potential new drivers for cancer is no longer a bottleneck. A major challenge, however, remains the rapid functional validation of the vast number of genes that were found mutated or lost. With regards to functional validation, in vivo modeling remains a state of the art discovery tool. However, the development of classical genetically engineered mouse models is cumbersome and time consuming, especially when several genetic drivers need to be combined. Our lab is using both traditional (stereotactic injection of modified neuronal stem cells) and more advanced (stereotactic injection of a CRISPR delivery system) in vivo modeling systems to screen cooperating candidate tumor suppressor and oncogenes that drive central nervous system tumors. A key element of both systems is that they are Fast, Flexible and Tractable. FAST, as validation and assembly of the constructs takes less than 2 weeks; FLEXIBLE, as up to 4 genes can be targeted in 1 reaction; TRACTABLE, as every modified cell will express luciferase, a marker easily traced with the IVIS imaging machine. These systems thus allow me to generate more genetically accurate mouse models for central nervous system tumors; moreover the well-controlled nature and in vivo setting of these experiments enables me to investigate and understand the interaction between different mutational events in human central nervous system tumors.
(2) Explore new therapies for central nervous system tumors
One of the most promising developments in recent years is the successful application of immunotherapy in the clinic. Excitingly, the potential success of immunotherapy for brain tumors is only just being explored. Pre-clinical experiments assessing the effect of immunotherapy can only be performed in immune-competent mice. Our mouse models will be ideal for testing immunotherapy in central nervous system tumors. Preliminary data in our MPNST model shows that BRD4 inhibition greatly improves the tumor immune microenvironment. Combining immunotherapy with BRD4 inhibition will be one of the first therapies to evaluate in my brain tumor mouse model. We are currently exploring if these therapies would also be effective against pediatric High Grade Gliomas.


(3) Investigate the activation of RAS transcriptional programs important for transformation
The RAS pathway is one of the most frequently deregulated pathways in cancer. Although RAS signaling cascades have been well studied, a complete picture of which transcription factors downstream of RAS and which direct target genes are important to drive transformation in MPNST and Central Nervous System Tumors is currently lacking. A profound understanding of the importance of these downstream factors will provide us with an unprecedented mechanistic insight into how the RAS transcriptional program is driven and how we can exploit this for the development of therapies. Recent technological innovations like, for example, the ability to use RNAi in an in vivo setting allow us to target transcription factors for the first time.

Summary
With the vast amount of sequencing data currently available, we can for the first time more accurately start to model the complexity of cancer. It is important for the cancer research community to conduct high quality basic research and to create tools that translate these basic biological findings into therapeutic opportunities that will benefit patients. Given our expertise in pre-clinical testing, epigenetics, immunotherapy and signaling biology our team is successfully contributing to this common goal.