Glioblastoma (GBM) remains among the most formidable cancers to treat, and current therapies, including radiation and temozolomide chemotherapy, have only palliative effects. Tumor recurrence occurs in virtually all patients, and relapsed tumors are more resistant to current cytotoxic therapies. Recent robust transcriptional profiling has classified GBM into 4 subtypes with distinct clinical features. In particular, mesenchymal (MES) GBM appears to be the most common subtype with the poorest prognosis. Nonetheless, the mechanisms that regulate growth of MES GBM cells have not been clarified. Among the heterogeneous cells in tumors, glioma stem cells (GSCs) are one of the, if not the only, critical therapeutic targets;however, subtype-specific GSCs are poorly characterized. Our preliminary data suggest the following: a- mesenchymal, but not proneural, GSCs express CD44v6;b- siRNA for CD44v6 reduces in vitro growth of MES, but not PN GSCs;c- CD44v6(+) cells but not CD44v6 (-) cells in mesenchymal GSCs express the neural stem cell-associated gene MELK;d- siRNA for CD44v6 reduces MELK expression;e- CD44 locus exhibits multiple Musashi 1 (Msi1)-binding sequences;f- shRNA- mediated Msi1 depletion diminishes CD44 expression and negatively affects splicing of exon v6. To achieve the goals of this study, we established and characterized patient-derived GBM sphere cultures and created patient-derived mouse GBM tumor models that recapitulate the histopathology of the original tumors. With these pre-clinical models, we will test the hypothesis that the Msi1-CD44v6 signaling is required for the growth and survival of therapy-resistant mesenchymal glioblastoma. Specifically, in Aim 1, we will test the hypothesis that CD44v6 is functionally essential for the proliferation of MES GSCs through signal interaction with MELK.
In Aim 2, we will determine whether CD44 transcripts are a direct target of the RNA-binding protein Msi1 in GBM and if Msi1 via the axis CD44v6-MELK plays a role in radio-resistance.

Public Health Relevance

The most common type of adult primary brain tumors, GBM is a devastating disease, and recurrence occurs in almost all patients. Although some cancers may not conform to the cancer stem cell model, evidence suggests that in GBM, glioma stem cells (GSCs) are responsible for glioma propagation, maintenance, resistance to conventional therapy, and tumor recurrence. This proposal will molecularly define GSCs by characterization of the key mechanism underlying proliferation of GSCs. We will further determine whether elimination of GSCs attenuates growth of tumors with the pre-clinical patient-derived GBM models.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O1))
Program Officer
Watson, Joanna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Medicine
United States
Zip Code
Nakano, Ichiro (2014) Therapeutic potential of targeting glucose metabolism in glioma stem cells. Expert Opin Ther Targets 18:1233-6
Feng, Haizhong; Lopez, Giselle Y; Kim, Chung Kwon et al. (2014) EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. J Clin Invest 124:3741-56
Nakano, Ichiro (2014) Proneural-mesenchymal transformation of glioma stem cells: do therapies cause evolution of target in glioblastoma? Future Oncol 10:1527-30
Ganguly, Ranjit; Hong, Christopher S; Smith, Luke G F et al. (2014) Maternal embryonic leucine zipper kinase: key kinase for stem cell phenotype in glioma and other cancers. Mol Cancer Ther 13:1393-8
Nakano, Ichiro (2014) Engulfing losers by winners in cancer: do cancer stem cells catch eat-me signals from noncancer stem cells? Future Oncol 10:1335-8
Nakano, Ichiro (2014) Transcription factors as master regulator for cancer stemness: remove milk from fox? Expert Rev Anticancer Ther 14:873-5
Kim, Sung-Hak; Kwon, Chang-Hyuk; Nakano, Ichiro (2014) Detoxification of oxidative stress in glioma stem cells: mechanism, clinical relevance, and therapeutic development. J Neurosci Res 92:1419-24
Minata, Mutsuko; Gu, Chunyu; Joshi, Kaushal et al. (2014) Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition. PLoS One 9:e92546