Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

Meenu Jain; Nipuni Dhanesha H. Gamage; Meshal Alsulami; Adarsh Shankar; Bhagelu Ram Achyut; Kartik Angara; Mohammad H. Rashid; Asm Iskander; Thaiz Ferraz Borin; Wenbo Zhi; Roxan Ara; Meser M. Ali; Iryna Oleksandrivna Lebedyeva; Wilson B. Chwang; Austin Guo; Hassan Bagher-Ebadian; Ali Syed Arbab

doi:10.1038/srep41809

Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

Meenu Jain, Nipuni Dhanesha H. Gamage, Meshal Alsulami, Adarsh Shankar, Bhagelu Ram Achyut, Kartik Angara, Mohammad H. Rashid, Asm Iskander, Thaiz Ferraz Borin, Wenbo Zhi, Roxan Ara, Meser M. Ali, Iryna Oleksandrivna Lebedyeva, Wilson B. Chwang, Austin Guo, Hassan Bagher-Ebadian, Ali Syed Arbab

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Abstract

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 αSMA), 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.

Original language	English (US)
Article number	41809
Journal	Scientific reports
Volume	7
DOIs	https://doi.org/10.1038/srep41809
State	Published - Jan 31 2017

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Jain, M., Gamage, N. D. H., Alsulami, M., Shankar, A., Achyut, B. R., Angara, K., Rashid, M. H., Iskander, A., Borin, T. F., Zhi, W., Ara, R., Ali, M. M., Lebedyeva, I. O., Chwang, W. B., Guo, A., Bagher-Ebadian, H., & Arbab, A. S. (2017). Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models. Scientific reports, 7, Article 41809. https://doi.org/10.1038/srep41809

Jain, M, Gamage, NDH, Alsulami, M, Shankar, A, Achyut, BR, Angara, K, Rashid, MH, Iskander, A, Borin, TF, Zhi, W, Ara, R, Ali, MM, Lebedyeva, IO, Chwang, WB, Guo, A, Bagher-Ebadian, H & Arbab, AS 2017, 'Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models', Scientific reports, vol. 7, 41809. https://doi.org/10.1038/srep41809

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title = "Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models",

abstract = "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 HP{\ss}CD 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 HP{\ss}CD-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 αSMA), in addition to inflammation and angiogenesis markers in the treatment group (p < 0.05). Our results indicate that HP{\ss}CD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, and neovascularization. Furthermore, HP{\ss}CD-HET0016 significantly prolonged survival in PDX GBM811 model.",

author = "Meenu Jain and Gamage, {Nipuni Dhanesha H.} and Meshal Alsulami and Adarsh Shankar and Achyut, {Bhagelu Ram} and Kartik Angara and Rashid, {Mohammad H.} and Asm Iskander and Borin, {Thaiz Ferraz} and Wenbo Zhi and Roxan Ara and Ali, {Meser M.} and Lebedyeva, {Iryna Oleksandrivna} and Chwang, {Wilson B.} and Austin Guo and Hassan Bagher-Ebadian and Arbab, {Ali Syed}",

note = "Publisher Copyright: {\textcopyright}The Author(s) 2017.",

year = "2017",

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day = "31",

doi = "10.1038/srep41809",

language = "English (US)",

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T1 - Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

AU - Jain, Meenu

AU - Gamage, Nipuni Dhanesha H.

AU - Alsulami, Meshal

AU - Shankar, Adarsh

AU - Achyut, Bhagelu Ram

AU - Angara, Kartik

AU - Rashid, Mohammad H.

AU - Iskander, Asm

AU - Borin, Thaiz Ferraz

AU - Zhi, Wenbo

AU - Ara, Roxan

AU - Ali, Meser M.

AU - Lebedyeva, Iryna Oleksandrivna

AU - Chwang, Wilson B.

AU - Guo, Austin

AU - Bagher-Ebadian, Hassan

AU - Arbab, Ali Syed

PY - 2017/1/31

Y1 - 2017/1/31

N2 - 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 αSMA), 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.

AB - 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 αSMA), 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.

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ER -

Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models

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