10038-ANGI-2 NEW ANTI-ANGIOGENIC THERAPY WITH THE ANTI-DEPRESSANT TOWARD TUMOR DERIVED ENDOTHELIAL CELLS (TDECS)
Hiroyuki Michiue, Nobushige Tsuboi, Yoshihiro Otani, Atsuhito Uneda, Yasuki Suruga, Matsumoto Yuji, Ishida Joji, Kentaro Fujii, Kazuhiko Kurozumi, Isao Date- Surgery
- Oncology
- Neurology (clinical)
Abstract
BACKGROUND
Anti-angiogenic therapy has been reported to prolong patient survival in some malignancies, but has not been shown to be effective in glioblastoma. We focused on the relationship between the differentiation of glioma stem-like cells (GSCs) into tumor-derived endothelial cells (TDECs) and resistance to anti-angiogenic therapy. In particular, we elucidated the mechanism of drug resistance of TDECs to anti-angiogenesis inhibitors, and identified and elucidated the efficacy of novel anti-angiogenesis inhibitors with potential clinical application.
METHODS
005 mouse GSCs were differentiated into TDECs under hypoxic conditions and analyzed by RNA-Seq over time. Furthermore, novel angiogenesis inhibitors for glioblastoma were evaluated by tube formation assay and existing blood-brain barrier permeable drugs. Novel angiogenesis inhibitors were administered in vitro to differentiated TDECs and in vivo to the 005 mouse brain tumor model and evaluated by RNA-Seq, immunohistochemistry, MRI imaging, and survival.
FINDINGS
In the GSCs005 brain tumor model, inhibition of the Vascular Endothelial Growth Factor (VEGF) pathway had no anti-tumor effect and conversely increased TDECs. A drug screening by Existing Drugs Redevelopment showed that the antidepressant sertraline inhibited TDEC tube formation. Sertraline decreased the expression of Lama4 and Ang2 in TDECs, which play an important role in non-VEGF-mediated angiogenesis in tumors. sertraline in combination with VEGF pathway inhibitors showed prolonged survival in the 005 model.
CONCLUSION
Diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways was shown to induce anti-angiogenic resistance. The combination of sertraline and VEGF pathway inhibitors with antidepressants was an effective anti-angiogenic therapy for glioblastoma and could be applied safely and cost-effectively.