Stem and progenitor cells in glial malignancies of the CNS.
Gliomas are the leading cause of cancer death in children, and the most common primary adult brain tumor. Aberrant signaling through EGFR features prominently in this disease. We therefore generated a mouse model for glioma, by over-expressing activated EGFR under control of the S100 beta promoter. These mice developed oligodendroglioma, and are being used to explore progenitor cells for this tumor in-vivo, to identify abnormal regions of proliferation in transgenic vs wt brains, and to isolate progentor populations by iterative dissociation, enrichment, and transplantation (into non-transgenic hosts). We have derived both neuropheres, and tumorspheres from these animals, and are actively characterizing and comparing these populations both functionally, and by standard in-vitro measures of proliferation, apoptosis, senescence, and expression profiling.
In related experiments, we are collaborating with the BTRC at UCSF to characterize a set of primary glioma tumors from patients. We are using established therapies for glioma in these primary cultures, to compare efficacy in primary cultures as a whole, with efficacy in progenitor cells in particular. In collaboration with Kevan Shokat, we are screening libraries of kinase inhibitors against these primary cultures to identify compounds active against progenitor cells, and kinase signatures associated with these activities.
Stem and progenitor cells in neuronal malignancies of the PNS.
Neuroblastoma is the third most common tumor of childhood. The proto-oncogene MYCN is amplified in one third of children with neuroblastoma. These tumors are generally incurable. We generated transgenic mice that over-express MYCN in the peripheral neural crest and develop neuroblastoma. We have extensively characterized the biology and genetics of malignant progression in this model, and have an ongoing program in preclinical therapeutics. Again in parallel with our work in glioma, we have derived tumorspheres from these animals, and are actively characterizing these cells, to better understand their biology, and to determine the importance of these cells (with regard to their sensitivitiy to targeted agents) in predicting response to therapy.