Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - TUMOR REPROGRAMMING (Targeting Glioblastoma Reprogrammed Stem Cells)

Glioblastoma (GBM) is the most common and lethal form of intracranial tumor. It represents one of the deadliest human cancers, with average survival at diagnosis of about one year. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. In the last century, we have accumulated tremendous amounts of data on this type of cancer, but despite extensive study, few therapeutic targets have been identified for GBM.
Mouse models of human cancers have been very instructional in understanding the basic principles of cancer biology, but they have not always been able to capture the complete extent of the human disease. Cancers arise from a single cell or a small number of cells in specific cell types, and the cellular origin of cancers is one of the major determinants of the characteristics of tumor cells. We have established a lentiviral-induced mouse model of malignant gliomas, which faithfully captures the pathophysiology and molecular signatures of human GBM. This mouse model of GBM is based on direct injections of Cre-inducible lentiviral vectors into the brain of mice which allows the induction of tumors in a region and a cell type specific manner in adult mice. Using this model we were able to show that gliomas can originate from differentiated cells in the central nervous system (CNS), including terminally differentiated neurons. We showed that transduction of neural stem cells (NSCs), astrocytes or even mature neurons can give rise to malignant gliomas. Based on these observations we propose that any cell in the brain can be the cell of origin of the tumors. In the case of mature neurons/glia, these cells acquire the capacity to dedifferentiate/reprogram to a cell that has all the attributes of a cancer stem cell. We proposed to employ the lentiviral-induced GBM mouse model together with advanced nanotechnology and immunology techniques to investigate the mechanisms of tumor reprogramming and the development of a novel therapeutic approach. In order to investigate the mechanism of tumor reprogramming we performed genome transcriptome analysis of the reprogrammed cells (in a cancer stem cell state) compared to their parental normal differentiated cells and found up-regulation of specific genes. We validated the expression of some of these genes in both murine and human GBM lines and started to inhibit their expression to assess their functional role in the process and evaluate their importance as possible therapeutic targets. In parallel, we used our previously identified homing peptide to tumor vasculature, CGKRK, to identify its receptor on the surface of tumor cells. We identified p32, a mitochondrial protein that is also expressed at the cell surface of activated (angiogenic) endothelial cells and tumor cells. Furthermore, we started to design a chimeric antigen receptor (CAR) in order to genetically engineered T cells to attack the glioma cells. Our findings will help understand the mechanisms of tumor reprogramming and design a novel therapeutic approach combining nanomedicine and adoptive cell therapy using genetic engineering T cells to enhance their antitumor capabilities and aim to kill glioma tumors.

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Life Sciences
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