Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Iimplicated Survival Benefit in Rat Xenograft Models
Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 is a selective CYP450 inhibitor, which has been shown to inhibit angiogenesis and tumor growth. Therefore, to explore novel treatments, we have generated an improved intravenous (IV) formulation of HET0016 with HPssCD and tested in animal models of human and syngeneic GBM. Administration of a single IV dose resulted in 7-fold higher levels of HET0016 in plasma and 3.6-fold higher levels in tumor at 60 min than that in IP route. IV treatment with HPssCD-HET0016 decreased tumor growth, and altered vascular kinetics in early and late treatment groups (p < 0.05). Similar growth inhibition was observed in syngeneic GL261 GBM (p < 0.05). Survival studies using patient derived xenografts of GBM811, showed prolonged survival to 26 weeks in animals treated with focal radiation, in combination with HET0016 and TMZ (p < 0.05). We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and alphaSMA), in addition to inflammation and angiogenesis markers in the treatment group (p < 0.05). Our results indicate that HPssCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HPssCD-HET0016 significantly prolonged survival in PDX GBM811 model.
Jain, M., Gamage, N., Alsulami, M., Shankar, A., Achyut, B., Angara, K., Rashid, M., Iskander, A., Borin, T., Wenbo, Z., Ara, R., Ali, M., Lebedyeva, I., Chwang, W., Guo, A., Bagher-Ebadian, H., & Arbab, A. (2017). Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Iimplicated Survival Benefit in Rat Xenograft Models. Scientific Reports, 7, 41809. https://doi.org/10.1038/srep41809