Intruigingly, these pHGG often have abberant activation of the RAS pathway. Given our interest in RAS pathway signaling and cancer, a subset of our research focuses on the RasGAP NF1. The NF1 gene is a tumor suppressor that negatively regulates RAS. NF1 is the causal gene of the common familial tumor predisposition syndrome Neurofibromatosis type I (NF1). NF1 patients develop an array of both benign and malignant central and peripheral nervous system tumors, all of which display aberrant RAS pathway activation. Of these, neurofibromas (benign), low-grade gliomas and Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are the most prominent; for none of these a cure exists. Importantly, NF1 is also frequently mutated in sporadic cancers such as glioblastoma multiforme (GBM), pediatric high grade gliomas, melanoma and lung cancer.

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 are 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. These systems thus allow us to generate more genetically accurate mouse models for central nervous system tumors.

We have a keen interest in investigating the cooperativity between loss of NF1 and mutations in the epigenetic machinery. Intriguingly, brain tumors often have mutations in epigenetic drivers.

Crucially, if we want to develop rational therapies for patients with pHGG we will have to study and understand the intricacies of how mutations in specific genes cooperate and discover which pathways are crucial for progression or therapeutic intervention. This focus on a basic research component is essential for success.

Our lab uses a multitude of techniques, ranging from RNAseq to ChIPseq, CRISPR and mouse modeling, to answer the “why” and “how” questions that are so crucial to enhance our understanding of what drives these pediatric brain tumors. Essential for these endeavors are research samples. Importantly, Children’s Hospital Philadelphia is the home of the CBTTC, the Children’s Brain Tumor Tissue Consortium, a consortium that collects, sequences and distributes samples and data of pHGG. Through the CBTTC we already have access to a wealth of the tumor samples needed for our research. 

We have a keen interest in investigating the cooperativity between loss of NF1 and mutations in the epigenetic machinery. A large portion of our work hence focuses on the question of how exactly these epigenetic drivers promote tumor formation in pHGG with NF1 loss.

If we want to develop and test effective therapies, there is a need to generate mouse models that can keep up with our continuously evolving understanding of the genetic and epigenetic events that drive cancer. Moreover, it is imperative that we not only generate genetically accurate mouse models for these gliomas but also phenocopy the tumor microenvironment (i.e. model pHGG in mice with an intact immune system) as the tumor microenvironment undoubtedly plays an important role during the formation of these tumors. Our mouse models will not only allow us to study the biology in vivo but will also allow us to test therapies (including immunotherapies) that, when successful, could be translated into clinical trials. Notably, we have over a decade of expertise in mouse modeling and pre-clinical trial development (De Raedt et al. Nature 2014) and our work has been translated into several clinical trials.

Infiltrating immune cells play an important role during glioma formation. Some of these immune cells have an anti-tumor function, importantly however, others actually protect and stimulate the glioma tumor cells. Crucially, we have developed mouse model of pHGG that accurately models human pediatric High Grade Gliomas and have both the infiltrating “good” (CD8 T-cells) and “bad” (microglia) immune cells.

We will test a combination therapy in these mice that, in addition to targeting the tumor cells directly, stimulates the CD8 T-immune cells while inhibiting the pro-tumor microglia immune cells.  If our approach is successful this therapy can quickly be translated into the clinic as all drugs used are approved or being used in clinical trials.

We have a keen interest in investigating the cooperativity between loss of NF1 and mutations in the epigenetic machinery. These epigenetic mutations often make tumors hyper sensitive to epigenetic based therapies. We have had a lot of success by using MEK (PD-0325901) in combination with BRD4 inhibitors (JQ1).