Targeting Spinal Ependymoma and Other Gliomas Using Novel Genetically Defined Models
Improved treatment of pediatric spinal cord gliomas will require better models to help us understand why these tumors form, and with which to test new therapies. Over the last 10 years, our understanding of the molecular changes which drive these tumors has improved, making it feasible to create such models using stem cells isolated from the fetal mouse spinal cord. We have introduced genetic drivers associated with spinal ependymoma, as well as low- and high-grade spinal astrocytoma, into murine spinal neural stem and progenitor cells. This resulted in increased overall growth, as well as increased ability of cancer “clones” to form in soft agar. These new tumor models also appear to be able to grow in mice. We have examined how gene expression changes in these new models and compared it to gene expression profiles in spinal gliomas from children. Similarities between our pediatric spinal ependymoma models and primary tumors suggest they can reproduce at least some of the human biology. We are particularly interested in the induction of a gene known as ARX, which is highly expressed in human pediatric spinal ependymoma but downregulated in adult ones. It is also induced many-fold in our mouse spinal ependymoma models, but not in the low- or high-grade astrocytoma models. We believe that ARX may represent a target for new “precision” treatments of pediatric spinal ependymoma.
Project Goal: We will now more fully validate our new spinal glioma models in culture systems and in animals, including a complete molecular and microscopic characterization. Some initial treatments will be tested in a “high throughput” culture system, which can be used to screen large drug libraries in the future. We will also optimize the growth of tumors in the brain and spinal cord of mice and zebrafish so that new drugs can be tested in a more realistic setting. Additional studies will examine the functional role of the gene ARX, to determine if it is a good therapeutic target in spinal ependymomas of children. Finally, we will generate a new model of a clinically aggressive pediatric spinal ependymoma subtype driven by amplification of a gene known as MYCN.
Project Update 2022: We have generated and completed initial validation of multiple novel spinal glioma models, driven by genes commonly altered in low grade gliomas, high grade gliomas, and ependymoma. This includes a new model of a clinically aggressive pediatric spinal ependymomas driven by amplification of a gene known as MYCN. These models have been used for initial testing of therapeutic agents, and we have identified small molecules targeting ATM as a new possible therapy for spinal ependymoma. Our ultimate goal is to advance new therapies to the clinic, and importantly many of these models generate xenografts in the brain suitable for preclinical testing. Additional studies will further examine possible new therapies in vivo.
