The most common adult brain cancer, glioblastoma (GBM) is incurable. Average survivals of 16-20 months have not improved significantly in decades underscoring the need for new approaches to therapy. The GBM stem cell (GSC) is a unique cell type within GBMs that is inherently resistant to treatments. In addition, heterogeneous mutations drive selection for treatment resistant GSC sub-populations within a tumor that drive progression. Here we propose a new strategy targeting GSCs based on leveraging their generic properties essential for maintaining their “identity” and malignant behavior. One such property, with great therapeutic potential, is the GSC cell membrane voltage potential, or ...

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The most common adult brain cancer, glioblastoma (GBM) is incurable. Average survivals of 16-20 months have not improved significantly in decades underscoring the need for new approaches to therapy. The GBM stem cell (GSC) is a unique cell type within GBMs that is inherently resistant to treatments. In addition, heterogeneous mutations drive selection for treatment resistant GSC sub-populations within a tumor that drive progression. Here we propose a new strategy targeting GSCs based on leveraging their generic properties essential for maintaining their “identity” and malignant behavior. One such property, with great therapeutic potential, is the GSC cell membrane voltage potential, or Vmem. Although a common feature of all cells, Vmem has specific values that distinguish between normal and cancer cells and further between stem-like treatment resistant GSC cancer cells and non-stem like and treatment responsive non-GSC cancer cells. Modulation of Vmem levels, achieved through ion channel activity also regulates malignant properties of GSCs including cell proliferation. We previously reported expression in GSCs of ion channels that can be targeted by ion channel modulating drugs to modify Vmem but these drugs have not been systematically screened for activity against GSCs. Therefore, we propose a novel high-throughput screening platform to identify ion channel drugs that simultaneously modulate GSC Vmem, cell proliferation and cell survival. Selected candidates will be validated in animal tumor models to identify drugs with clinical potential. This multi-disciplinary project brings together experts in glioma biology, neuroscience and drug screening and is expected to establish Vmem as a critical phenotype regulating GSC malignancy that overcomes current obstacles of resistance and heterogeneity. Future preclinical and clinical trials will then validate the therapeutic potential of selected ion channel drugs alone or as adjuncts to other therapies.

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