Abstract 2935: Novel combination of repurposed drugs induces complete cell invasion arrest of glioblastoma in vitro

Abstract

Abstract Introduction: Glioblastoma multiforme (GBM) is an aggressive and lethal cancer with a poor prognosis even after conventional treatment (surgery, radiation, chemotherapy). Temozolomide (TMZ) is a standard cyotoxic agent used, despite resistance leading to recurrence. Therefore, additional strategies for targeting the tumor environment are needed. We demonstrate a combination of approved drugs (CAD) repurposed to target GBM leads to complete arrest of GBM cell invasion. Each drug in the combination individually targets diverse tumor pathways: 1) invasion via MMP2 (doxycycline); 2) angiogenesis, inflammation, and proliferation via p53-dependent G1 cell-cycle arrest (celecoxib); 3) autophagy (tamoxifen); 4) tumor metabolism and angiogenesis (metformin). Material and Methods: Multicellular Tumor Cell Spheroids (MTCS) were generated from two GBM cell lines (LN18, U87MG) and embedded in collagen (three-dimensional in vitro assay) and mixed with the drug combination at 2 doses + TMZ. GBM cell invasion was monitored and quantified over 96h. Flow cytometry analysis using Propidium-Iodine was performed (24h, 48h, 7h2 and 96h) to quantify the effect of the drug cocktail. Scanning Electron Microscopy (SEM) of MTCS was used to evaluate cell death at the ultrastructural level (96h after treatment). Results: The CAD induced complete cell invasion arrest in both U87MG and LN18 MTCS regardless of drug dose or presence of TMZ. GBM cell death was observed after 96h. TMZ in combination with CAD showed a significant increase in cell death, suggesting synergism. SEM images demonstrated large-scale changes in the tumor spheroid morphology showing GBM cell death. Conclusions: The combination of approved drugs (CAD) with TMZ can effectively halt GBM cell invasion and induce cell death in vitro. These results suggest a sensitizing effect of CAD to potentiate TMZ’s effects. Because CAD components have well established safety profiles, further investigation to define the anti-GBM mechanisms and effects on the tumor microenvironment are warranted. This CAD has potential for future therapeutic approaches. The generic nature of the drugs makes CAD an intriguing cost-effective GBM adjunctive therapy. Citation Format: Liliana Oancea-Castillo, Kerstin Bahr, Anne Régnier-Vigouroux, Maximilian Ackermann, Isaac R. Gabriel, Samuel T. Pereles, Madeleine M. Li, Dana W. Lowitt, William W. Li, Vincent W. Li. Novel combination of repurposed drugs induces complete cell invasion arrest of glioblastoma in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2935.