My laboratory has performed basic and translational neuro-oncology research for nearly 15 years. We described the first intracranial models of medulloblastoma and glioblastoma for bioluminescence imaging and used them to demonstrate the in vivo efficacy of CXCR4 antagonism. Since that time, we have defined the role of CXCR4 in mediating functions of the glioblastoma and medulloblastoma perivascular stem-like cell niche. CXCR4 functions to suppress cAMP levels and we have also described cAMP elevation for the treatment of medulloblastoma and high and low grade astrocytoma. CXCR4 induced cAMP suppression appears to be essential for maintaining the pool of stem-like cells in medulloblastoma. We defined CXCR4 subtypes within the sonic hedgehog subgroup of medulloblastoma and believe these will be important for patient stratification in clinical trials of combined CXCR4 and sonic hedgehog antagonism.
More recently, we have been investigating the molecular basis for sex differences in brain tumors. Regardless of age, more males get brain tumors and overall they exhibit shorter progression-free survival than females. In children with glioblastoma, the effect of sex on outcome can be greater than the effect of standard of care therapeutics. We were the first to report that cell intrinsic sexual dimorphism in key tumor suppressor pathways contributes to sex differences in glioblastoma. This new focus has included development of model systems and an evaluation of the role that epigenetics play in sexual differentiation and the genesis of brain tumors, as well as in response to chemotherapy. It is our hope that a focus on the mechanisms that protect females from the development of brain tumors and improve their outcome will reveal novel therapeutic targets that can be employed in the treatment of anyone with a brain tumor.
In our work, we utilize primary patient derived specimens and genetically engineered mouse models for in vitro and in vivo studies. In addition to routine approaches in cancer cell biology, we perform genome editing with CRISPR/CAS9, RNA and DNA sequencing, chromatin immunoprecipitation and assays of stem cell function. We are involved in multiple collaborations with investigators from the Departments of Developmental Biology, Neurosurgery, Genetics and Radiology. Our scientific research is complemented by my positions as co-director of the St Louis Children’s Hospital clinical neuro-oncology program and pediatric brain tumor bank and Co-Leader of the Neuro-Oncology Focus Group of the Alvin J Siteman Cancer Center.