Abstract
Abstract Glioblastoma Multiform (GBM) is one of the most aggressive and lethal types of all cancers with a median survival of about one year and a very low 5-year survival rate of 5% among the patients. Therefore, development of effective treatments for GBM is constantly needed. Since GBM is one of the most highly vascularized solid tumors, and its growth is angiogenesis- dependent, antagonizing tumor angiogenesis by using anti-angiogenic agents seems to be a promising strategy for treating GBM. However, one of the difficulties that limit the usage of angiogenesis inhibitors for brain tumor treatment is the presence of the BBB (Blood-Brain Barrier). In this context, F16, a novel anti-angiogenic agent developed at the Rumbaugh Goodwin Institute for Cancer Research of Nova Southeastern University, has shown promising results. Intensive preclinical evaluation of F16 had exhibited potent anti- angiogenic and anti-tumor activities via selectively antagonizing VEGFR2 in HUVEC (Human Umbilical Vascular Endothelial Cells) and also in xenograft tumor models. More importantly, we evaluated F16 pharmacokinetic distribution patterns using BALB-c mice. After a single i.p injection, F16 concentration was the highest in the brain indicating that F16 was transported across the BBB and was slowly accumulating in the brain. Even though there was a measurable accumulation of F16 in the brain, no signs of cognitive changes or behavioral alterations were observed in the treatment groups. Assessment of biochemical parameters that are reflecting vital organ functions showed no signs nor elevation in injury related biomarker levels of liver, heart, kidney, and pancreases after F16 treatment. Our preliminary in vitro studies of F16 on U87MG cell lines showed that F16 exhibited potent cytotoxicity against U87MG cell lines with the IC50 value of 26 μM. Furthermore, western blot results of U87MG showed an increase in the expression of BAX, p53 and p21 after treatments with 10 μM and 20 μM of F16. In addition, F16 inhibited the migration of U87MG cells after 24 h of treatment. Our experiments with intracranial Glioblastoma xenograft model exhibited significant regression of the tumor in both F16 and F16 + TMZ (Temozolomide) combination treated animals. Therefore, our results suggest that F16 could reduce tumor growth in monotherapy as well as in combination with TMZ and extend the survival of the tumor bearing animals. (This research was supported by the generous funds provided by the Community Foundation of Broward, Florida and the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida). Citation Format: Appu Rathinavelu, Mohammad Mansour Algahtani, Umamaheswari Natarajan, Jayanta K. Das, Thiagarajan Venkatesan. A novel anti-angiogenic agent F16 for the treatment of glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6359.
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