Glioblastoma multiforme (GBM) is the most common malignant intracranial tumor in adults. Despite the knowledge of the genetic alterations associated to GBM and the improvement in neurosurgery and chemo- and radiotherapy, little improvement has been achieved in the median survival. Recently, glioma stem cells (GSCs) have been identified to be responsible of the origin, recurrence and drug resistance in GBM, constituing so an attractive therapeutic target in the fight against gliomas. The present project aims to study the biology of GSCs and characterize their genomic and transcriptomic in response to inhibitors of the Notch pathway. This pathway has been demonstrated to be very important in glioma and alterations in components of this pathway have been identified in GBM. The research line proposed here will be multidisciplinary and in close contact with the patient. The objectives of the present project are:
1. Isolation of GSC from clinical samples obtained after brain surgery through sorting for stem cell markers and characterization by SNP arrays, RT-PCR, CGH, etc.
2. Analysis of the response to Notch inhibitors in GSCs ex vivo and in vivo. Analysis of the status of this pathway in GSC and the response to Notch inhibitors in culture (proliferation, apoptosis, neurosphere formation, differentiation, etc) and in vivo after injection of GSCs intracranially into mice. Gene expression analysis of tumors treated with Notch inhibitors in order to identify genes associated with response to treatment.
3. Test of candidate genes involved in resistance to treatment in vitro and in vivo. By blockade using RNA interference or inhibitors.
4. Clinical correlation. Results obtained in the laboratory will be correlated with clinical data from patients involved in the Notch inhibitor clinical trial in our Hospital.
Since this GSCs share characteristics with other cancer stem cells, such as colon and breast, the results of this study can be extrapolated to other tumor types.
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