Glioblastoma Multiforme (GBM) is a lethal brain tumor that typically causes death within 2 years after initial diagnosis. GBM accounts for 25% of all primary brain tumors in adults. Despite improvements in precise surgical de-bulking, radiation, and drug therapy, the prognosis for GBM patients has not significantly changed in decades. Novel therapies are therefore desperately needed. Recent studies have revealed that similar to leukemia, a glioma is a heterogeneous tumor comprised of differentiated tumor cells and cancerous progenitor cells known as """"""""brain tumor stem cells"""""""" (BTSCs). It has been demonstrated that BTSCs account for a minor fraction of total tumor cells, but are the only cells within the tumor mass that are capable of tumor renewal and tumor recurrence. These findings have significance because they suggest that novel therapy should be designed to selectively target BTSC, rather than conventional approaches that target the bulk tumor mass. We have discovered the BTSCs may be invisible to the immune system because they lack expression of cell surface receptors needed for both innate and adaptive immune-mediated killing. Treatment of BTSCs with interferon gamma (INF-y) restores their immunogenicity and susceptibility to being killed. We are moving forward with our Sleeping Beauty (SB) Transposon plasmid-based gene transfer system for treatment of brain tumors with INF-y gene therapy. In contrast to conventional plasmid DNA vectors, SB mediates sustained gene expression in glioma cells and therefore has potent anti-tumor efficacy. In parallel, we will develop and test a novel BTSC-targeted plasmid delivery vector by conjugating polyethylenimine (PEI) transfection reagent with anti-CD133 antibody because BTSCs express the CD133 receptor but their daughter cells do not. PEI/DNA/CD133mAb complexes will be used to deliver a potent suicide gene into an improved, invasively growing mouse model of GBM alone, or in combination with SB-mediated INF-y gene therapy. We contend that the combination of BTSC-targeted cell death with sustained INF-y mediated immune stimulation will provide a breakthrough in brain tumor immunotherapy by evoking an immune response that eliminates residual BTSCs. This project will initiate the commercialization of these 2 drugs for GBM therapy.
In Aim1, we will develop and optimize BTSC-targeted gene delivery by perfecting PEI/DNA/CD133mAb complexes. These experiments will be done in vitro using human GBM tumor samples to produce a targeted drug for a phase I clinical trial.
In Aim 2, the efficacy of SB-mediated INF-y gene therapy and BTSC-targeted suicide gene therapy will be evaluated in vivo in preparation for large animal studies and eventual IND application. Completion of these studies is crucial to accelerate commercialization of SB and BTSC-targeted gene therapy vectors, in order to meet our goal of providing safe and effective gene therapy for treatment of patients with fatal brain tumors. There is currently no effective therapy for patients with glioblastoma, a lethal brain tumor that accounts for 25% of primary brain tumors in adults. Most patients die within 2 years after diagnosis and over 10, 000 people die each year from glioblastoma in the United States alone. In this project, we will develop and begin to commercialize a novel form of gene therapy that is intended to destroy rare """"""""tumor stem cells"""""""", which are the cells that ultimately kill glioblastoma patients. ? ? ?
| Wu, Anhua; Oh, Seunguk; Wiesner, Stephen M et al. (2008) Persistence of CD133+ cells in human and mouse glioma cell lines: detailed characterization of GL261 glioma cells with cancer stem cell-like properties. Stem Cells Dev 17:173-84 |
| Wu, A; Oh, S; Ericson, K et al. (2007) Transposon-based interferon gamma gene transfer overcomes limitations of episomal plasmid for immunogene therapy of glioblastoma. Cancer Gene Ther 14:550-60 |
