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2006
Keith Rich, M.D.
Washington University
Transglutaminase 2 inhibitor, KCC009, sensitizes glioblastomas to chemotherapy
This research characterizes an enzyme, transglutaminase 2 (TG2), expressed in increased amounts in malignant brain tumors. Dr. Rich and his team will assess TG2 as a target in clinical treatment of malignant brain tumors. Treatment of glioblastoma cells in the laboratory with the novel small molecule inhibitor of TG2, KCC009, increases the effects of subsequent chemotherapy in killing tumor cells.
Dr. Rich and his colleagues reported the ability of KCC009 to sensitize glioblastomas to chemotherapy in experiments with multiple human glioblastoma cell cultures and in two experimental animal brain tumor models. They also identified the suspected mechanism of action whereby KCC009 enhances tumor cell death.
Dr. Rich and his team hypothesize that KCC009 treatment results in the disruption of the protein, fibronectin at the cell surface of glioblastomas. Fibronectin is important in remodeling the protein interface at the cell surface in brain tumor cells, a key step in promoting resistance to clinical treatment with chemotherapy.
His laboratory will characterize brain tumors induced in genetically altered mice that either express or fail to express the TG2 protein and in transplantation models of human glioma. These studies will enable them to determine the specific role TG2 plays in development of glioblastomas and in promoting tumor-resistance to chemotherapy. They will test the additive effects of dual combination therapy with KCC009 and several chemotherapy agents and targeted therapy
The overall goal of this project is to further validate KCC009 as a novel, potentially useful clinical therapy for GBM patients. The aspiration is to initiate clinical trials in the next 18 months.
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