Glioblastoma (GBM), the most common type of malignant brain cancer, is uniformly fatal despite ongoing research into the development of novel therapeutics. One reason for the high lethality of GBM is the presence of a self-renewing population of cells that is resistant to chemo- and radiation therapy, termed cancer stem cells (CSCs). Although the cancer stem cell hypothesis remains controversial, we and others have shown that directly targeting this population of cells decreases tumor growth and initiation and sensitizes tumors to current clinical therapies. Cellular interactions within the CSC compartment and between CSCs and non-CSCs help maintain the balance between CSC self-renewal and differentiation. Direct cell interactions may also allow cells to rapidly adapt in response to tumo growth and the presence of chemotherapeutics. Gap junctions, one type of cell-cell contact mechanism, are composed of connexin subunits that form connexon channels, which allow the transport of small molecules from cell to cell. The translational goal of this project is to conduc mechanistic studies into the role of cell-cell interactions in the progression of GBM. We hypothesize that cell type-specific communication is controlled by a balance of connexin subunits and that disrupting this balance attenuates GBM progression. We will interrogate this hypothesis by investigating the following aims: 1) that the balance between connexin subunits exerts differential effects on CSCs, non-CSCs, and normal neural cells; 2) that Cx46 contributes to CSC maintenance; and 3) that in vivo targeting of connexin subunits attenuates GBM progression. The long-term goal of this project is to translate the information gained about direct cell-cell communication in GBM to inhibition strategies useful as clinical therapies.

Public Health Relevance

Advances in cancer treatment have thus far failed to successfully treat glioblastoma patients or extend survival beyond the median 12-15 months. The severity of glioblastoma is due at least in part to a self-renewing population of chemo- and radio-resistant cells termed cancer stem cells. Communication within the cancer stem cell population and between stem cells and non-stem cells may be a novel mechanism against which to direct next-generation therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS089641-04
Application #
9552265
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2015-09-30
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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