Investigators

Summary

Brain Tumor Metabolism and Functional Cancer Genomics Laboratory
Laboratory of brain tumor metabolism and functional cancer genomics laboratory are established and directed by Dr. Antony MichealRaj in September 2021 at the Department of Neurological Surgery, University of Pittsburgh School of Medicine.
We are focused on exploring the underlying disease mechanism of pediatric brain tumors, with a specific interest in pediatric cancer stem cells- brain tumor metabolism and epigenetics and post transcriptional and translational regulation. Our team is investigating following major themes in pediatric ependymomas and gliomas:
1) Functional cancer genomics using in vivo and In vitro CRISPR screens
2) Metabolic dependencies and epigenetic regulation in primary and recurrent tumors
3) Unraveling the crosstalk between cell signaling and epigenetics
4) mRNA regulation and translational control

Since September 2021, the Brain Tumor Metabolism and Functional Cancer Genomics Laboratory explored the molecular network and metabolic dependencies which are essential for pediatric supratentorial ependymomas survival and proliferation. Supratentorial ependymomas (ST-EPNs) are aggressive pediatric forebrain malignancies, which account for 40% of all intracranial ependymomas. Recurrent fusion of ZFTA (previously known as C11orf95) with RELA or other genes such us YAP1, MAML2, MAML3, NCOA2 are identified to be oncogenic drivers of Supratentorial ependymoma which does not have an effective therapeutic option. Up to 40% of children with this Ependymoma succumb to their disease, and survivors are often left disabled because of toxicity from the tumor and treatment. We have made reasonable progress on identifying the abnormal gene elements that could potentially drive this lethal tumor. However, we are still far behind in understanding the molecular network which makes children vulnerable to this tumor. Unraveling this network is very important for novel therapeutic interventions. We have developed disease models from supratentorial ependymoma patients and applied cutting- edge scientific tools to target one gene at a time on a genome-wide scale. In parallel, we have profiled the surgical biopsies abnormal gene expression and protein levels. Through these analyses, we have identified genes that are not mutated but are very important for tumor development. This essential genetic network unraveled the potential cell of origin and suggest the putative oncogenic route of this neoplasm. Additionally, our metabolic profiling and tracing studies in disease models identified the nutrient demand that are required for epigenetics, macromolecular synthesis and bioenergetic processes in supratentorial ependymomas. We are now exploring single and combined therapeutic approaches to target this tumor by blocking the metabolic activity by selective and blood brain penetrant small molecules and nutrient limited- diet. For the first time, we established a transgenic mouse model for supratentorial ependymoma which will be used as primary tool for investigating disease mechanism and novel therapeutic discoveries/validations.
Our team using patient-derived disease models (Cell lines, Xenografts) and transgenic mouse models and cutting edge next-generation genomic technologies (Bulk and single cell sequencing, ChIP seq, long read sequencing), metabolomics (total and targeted), genetic engineering tools (Genome-wide and focused CRISPR screen) to advance our existing knowledge on pediatric brain tumors and probe novel therapeutic options.