DDRE-06. REGULATION OF TUMOR MICROENVIRONMENT VIA ENDOTHELIAL-TO-MESENCHYMAL TRANSITION BLOCKADE IN GLIOBLASTOMA-ASSOCIATED BRAIN ENDOTHELIAL CELLS

Glioblastoma multiforme (GBM) is a malignant brain tumor noted for its extensive vascularity, aggressiveness, and highly invasive nature. Glioma stem cells (GSC) are a subpopulation of cells resistant to treatments and considered responsible for tumor recurrence. GSC are found in the vascular niches of the tumors, where endothelial cells (EC) secrete factors that stimulate GSC self-renewal. There are several studies regarding the effects of the vasculature on CSC and tumorigenesis, but little is known about how GSC affects the vasculature. Resistance to therapies and tumor recurrence greatly rely on the pro-angiogenic nature and aberrant vasculature of GBM. The endothelial-to-mesenchymal transition (EndMT) supports the pro-angiogenic and invasive characteristics of GBM. Hence, blocking the EndMT would be a promising approach to inhibit tumor progression and recurrence. We have examined the dynamic cross-talk between GSC and EC during EndMT. We demonstrate that GSC induce EndMT in brain endothelial cells (BEC), through a collaboration between TGF-β and Notch pathways, nicotinamide N-methyltransferase upregulation and other key signaling routes. Elucidating the cells and molecular pathways responsible for this process represents a milestone in the understanding of the tumor microenvironment and will help develop novel treatments in glioma therapy. One promising treatment, developed by our research group, is the conjugate of temozolomide and perillyl alcohol (POH), NEO212. This drug blocks EndMT induction in BEC and reverts the mesenchymal phenotype of tumor-associated BEC (TuBEC), reducing the invasiveness and pro-angiogenic properties of GBM in vitro and in vivo. We are currently performing Investigational New Drug (IND)-enabling studies, and we foresee that NEO212 will be of great clinical value for the treatment of GBM.