EVALUATION OF F16 AS A NOVEL ANTIANGIOGENIC AGENT FOR GLIOBLASTOMA TREATMENT

Abstract

Glioblastoma multiforme (GBM) is one of the most aggressive and lethal types of brain cancers with a low 5-year survival rate. Therefore, searching for better drugs and effective treatment strategies for GBM to improve patient outcomes is continuing. Since GBM is one of the most highly vascularized solid tumors and its growth is angiogenesis-dependent, antagonizing tumor angiogenesis by using angiogenesis inhibitors is considered as a promising approach for treating GBM. In this context, intensive preclinical evaluation of our patented antiangiogenic compound, code-named F16, has exhibited potent antiangiogenic and anti-tumor activities via selectively antagonizing VEGFR-2 in both in vitro and in vivo models. More importantly, the pharmacokinetic distribution of F16 showed that F16 was transported across the BBB and slowly accumulated into the brain regions with no signs of toxicity. Hence, preclinical studies have been conducted to determine the efficacy of F16 in delaying glioblastoma progression via inhibiting tumor angiogenesis. In addition to the antiangiogenic properties, our in vitro studies have confirmed potent inhibitory effects of F16 towards the migration and invasion of U87MG cells, and also revealed potent cytotoxic effects (IC50 26 µM) against U87MG cells in comparison to temozolomide (IC50 430 µM) treatment. Subsequent to competitive receptor binding, F16 inhibited the phosphorylation of VEGFR-2 that was leading to cell cycle arrest and apoptosis by upregulation of p53, p21, and Bax in U87MG cells. Furthermore, our in vivo results with the ectopically implanted xenograft model confirm the fact that F16 can significantly inhibit tumor growth in the mice implanted with U87MG GBM cell line. Similarly, results obtained from the intracranial study proved good potency of F16 treatment in inhibiting tumor growth and prolonging the median survival of mice implanted intracranially with U87MG-Luc cells. Unlike TMZ, our toxicity study revealed that F16 was well tolerated in mice without evidence of significant toxicities. Moreover, a significant reduction of CD31 expression was observed in F16 tumor sections compared to tumor sections from TMZ treated mice, indicating that F16 effectively blocked angiogenesis in vivo. Based on our findings, we are proposing that F16 is a good candidate for treating GBM, either in monotherapy or in combination with a cytoreductive drug.