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, but also to use advanced in vivo models and tools to functionally identify and understand how epigenetic mutations cooperate with RAS pathway activation. Additionally, we have a keen interest in developing novel therapeutic approaches, including cellular and immunotherapies.

(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. We stereotacticly inject in vitro modified neuronal stem cells and glioma stem cells to screen cooperating candidate tumor suppressor and oncogenes that drive central nervous system tumors in vivo. Hereby we are generating 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. Currently we are focusing on 2 epigenetic regulators (SETD2 and ATRX) and how they cooperate with NF1 loss (RAS pathway activation).

(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) Development of novel cellular therapies for glioblastoma: Cellular therapies, like CAR-T therapy, have revolutionized the treatment of some cancers. Unfortunately, CAR-T has shown limited efficacy for brain tumors, due to the lack of unique tumor antigens, the downregulation of targeted antigens, and the immune suppressive tumor microenvironment (TME). To circumvent these brain tumor specific obstacles, we developed a cellular immunotherapy delivery system, derived from post-mitotic Migratory Cortical Inhibitory Interneuron Precursors (MCIPs), that induces a cytotoxic tumor response in glioblastoma independent of unique tumor antigens.
In all mammals studied, the inhibitory interneurons of the cerebral cortex originate entirely, or at least predominantly, in the ventral/subcortical portion of the telencephalic neural tube. The embryonic and early postnatal migration into and through the cerebral cortex is guided by a variety of chemorepulsant and chemoattractant factors. Remarkably, MCIPs maintain their migratory capacity when transplanted into the postnatal cerebral cortex, striatum, cerebellum, and spinal cord. This capacity has led to many preclinical and a first human trial of MCIP transplantation as cell based therapy for intractable epilepsy.
Intriguingly, glioblastoma frequently secrete the same chemoattractant factors, such as CXCL12, used by MCIPs to guide their migration during development. Indeed, our in vitro and in vivo data show that MCIPs robustly migrate to the majority of glioblastoma evaluated. This inspired us to modify MCIPs to serve as a delivery vector for cytotoxic agents that can eliminate glioblastoma. For example, EGFR-BiTE (Bispecific T-cell Engager) secreting MCIPs eliminate EGFR expressing glioblastoma both in vitro and in vivo. Bispecific Engagers are in essence two antibodies linked together, where one antibody binds to a tumor antigen and the other binds to an antigen on, for example, a T-cell or macrophage. Engagement with a bispecific antibody activates the immune cell.


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, cellular and immunotherapies and signaling biology our team is successfully contributing to this common goal.