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 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.
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Meenu
authors.initials: M
authors.lastname: Jain
authors.affiliation: Cellular and Molecular Imaging Laboratory, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Nipuni-Dhanesha H
authors.initials: NH
authors.lastname: Gamage
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Meshal
authors.initials: M
authors.lastname: Alsulami
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Shankar
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Bhagelu R
authors.initials: BR
authors.lastname: Achyut
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Kartik
authors.initials: K
authors.lastname: Angara
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Rashid
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Asm
authors.initials: A
authors.lastname: Iskander
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Thaiz F
authors.initials: TF
authors.lastname: Borin
authors.affiliation: Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wenbo
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Roxan
authors.initials: R
authors.lastname: Ara
authors.affiliation: Cellular and Molecular Imaging Laboratory, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Meser M
authors.initials: MM
authors.lastname: Ali
authors.affiliation: Department of Chemistry and Physics, Augusta University, Augusta, GA, USA.
authors.forename: Iryna
authors.initials: I
authors.lastname: Lebedyeva
authors.affiliation: Cellular and Molecular Imaging Laboratory, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Wilson B
authors.initials: WB
authors.lastname: Chwang
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Guo
authors.affiliation: Cellular and Molecular Imaging Laboratory, Henry Ford Health System, Detroit, MI, USA.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bagher-Ebadian
authors.affiliation: Tumor Angiogenesis Laboratory, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
mesh_terms: D000199:Actins / Q000378:metabolism; D061605:Administration, Intravenous; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000199:Actins; D065607:Cytochrome P-450 Enzyme Inhibitors