ZIA BC 011649 (ZIA) | |||
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Title | The Hippo Pathway in Human Gliomas | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Stommel, Jayne | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $158,514 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Brain (100.0%) Nervous System (100.0%) |
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Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Endogenous Factors in the Origin and Cause of Cancer |
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Abstract | |||
Glioblastoma Multiforme (GBM) is an extremely aggressive brain cancer characterized by rapid progression, high resistance to current therapeutic regimens, and survival rates of only 25% two-years post diagnosis. These characteristics of GBM are attributed to glioblastoma stem cells (GSCs), a highly tumorigenic subpopulation of cancer stem cells that have been identified as the true therapeutic targets for the treatment of GBM. Along these lines, previous studies have attempted to exploit the prevalent amplification and/or mutation of receptor tyrosine kinases (RTKs) within GSCs by treating these cells with tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor alpha (PDGFRA). Although these studies have demonstrated that TKIs are highly effective at reducing cell proliferation in sparse cell populations in vitro, their efficacy in the clinic has been limited. The mechanism underlying this acquired resistance to TKIs in vivo remains to be elucidated. We have data that demonstrate that high cell density in vitro can recapitulate the resistance to TKIs observed in vivo. In recent years, studies have suggested that dysregulation of the Hippo pathway may underlie the progression of cancer, poor overall patient survival and treatment resistance. Since high grade gliomas are positively correlated with expression of TAZ and therapeutic resistant stem cells give rise to GBM, we hypothesize that dysregulation of the Hippo pathway in cancer stem cells may play a significant role in the propagation and sustainment of GBM. Loss-of-function studies using shRNAs against TAZ in GSCs were used to delineate the role of TAZ in high density-dependent drug resistance and tumorigenesis in GBM. Gain-of-function studies using overexpression of TAZ in immortalized normal human astrocytes (NHAs) were used to determine if overexpression of TAZ confers dysregulation of the Hippo pathway that may induce tumorigenic characteristics to nontumorigenic neuroglial cells. Our studies suggest that TAZ is functionally associated with density-dependent resistance to TKIs and multiple tumorigenic characteristics of glioblastoma stem cells. Furthermore, the tumorigenic properties acquired by immortalized NHAs in the presence of TAZ, suggest that dysregulation of the Hippo pathway via overexpression of TAZ may drive transformation of normal neuroglial cells into cancerous cells. An increased understanding of the molecular interactions underlying the functional role of TAZ in density-dependent drug resistance and tumorigenesis will help identify novel therapeutic targets for the treatment of GBM. |