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Glioblastoma multiforme is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature, suggesting that cell migration plays an important role in tumor progression. The poor prognosis in GBM is associated with a high rate of tumor recurrence, and resistance to the standard of care chemotherapy, temozolomide (TMZ). Neonc Technologies Holdings, Inc.’s novel compound NEO212, a conjugate of TMZ and perillyl alcohol (POH), has proven to be 10-fold more cytotoxic to glioma stem cells (GSC) than TMZ, and is active against TMZ-resistant tumor cells.
In this study, Neonc was able to show that NEO212 decreases migration and invasion of primary cultures of patient-derived GSCs, in both mesenchymal USC02 and proneural USC04 populations. The mechanism by which NEO212 reduces migration and invasion appears to be independent of its DNA alkylating effects, which cause cytotoxicity during the first hours of treatment and are associated with a decrease in the FAK/Src signaling pathway, an effect not exhibited by TMZ. NEO212 also decreases the production of matrix metalloproteinases MMP2 and MMP9, crucial for GSC invasion.
Gene expression analysis of epithelial and mesenchymal markers suggests that NEO212 increases the expression of epithelial-like characteristics, suggesting a reversion of the epithelial to mesenchymal transition process. Furthermore, in an in vivo orthotopic glioma model, NEO212 decreases tumor progression by reducing the invasion of GSCs, thereby increasing the survival time of mice. These studies indicate that NEO212, in addition to cytotoxicity, can effectively reduce migration and invasion in GSCs, thus exhibiting significant clinical value in the reduction of invasion and malignant glioma progression.
With this study, Neonc has shown that its NEO212 formulation can block GSC migration and invasion in vivo as well as its selective cytotoxicity of tumor cells, and as a result, NEO212 is an ideal candidate for the treatment of newly diagnosed and TMZ-resistant gliomas.
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NEO212 Inhibits Migration and Invasion of Glioma Stem Cells.
Authors: Nagore I. Marín-Ramos1, Thu Zan Thein1, Hee-Yeon Cho1, Stephen D. Swenson1, Weijun Wang1, Axel H. Sch€onthal2, Thomas C. Chen1,3, and Florence M. Hofman1,3
2Department of Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California.
3Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California.