Abstract 2863: Magnetic resonance imaging based analysis of tumor growth and vascular parameters in animal model of GBM following IV formulated of HET0016 treatments

Abstract

Abstract Glioblastoma (GBM) is a hypervascular primary brain tumor with poor prognosis. HET0016 a selective CYP450 inhibitor 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. Tumor growth and vascular parameters (tumor blood volume, permeability and, extravascular and extracellular space volume) were determined by in vivo dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). The pharmacokinetics of HPßCD-HET0016 were evaluated in plasma and tumor tissues using IV and IP routes of administration. IV treatment with HPßCD-HET0016 decreased tumor growth, tumor blood volume, permeability and, extravascular and extracellular space volume, when compared with the vehicle group (p<0.05). Similar growth inhibition was also observed in syngeneic GL261 GBM (p<0.05). Survival studies using patient derived xenografts of GBM (PDX), showed prolonged survival to 25-27 weeks in animals treated combinedly with focal radiation, IV HET0016 and TMZ (p<0.05). Administration of a single dose resulted in 7-fold higher levels of HET0016 in the IV group in plasma and 3.6-fold higher levels in tumor tissue at 60 min compared to that of IP route. We observed reduced expression of markers of cell proliferation (Ki-67), decreased neovascularization (laminin and αSMA) and migration (MHC-1) in the treated group (p<0.05). Decreased tumor growth was associated with reduced expression of pro-angiogenic markers (IL-8, MCP-1, VEGF, HIF-1α, and VE-Cadherin), inflammation (p-NFκB), intermediates of MAPK pathway (p-AKT, p-ERK and p-STAT1, EGFR), arachidonic acid metabolism (COX-1, CYP4A11) and increased expression of anti-angiogenic markers (Ang2, Angiostatin and Tie-2). Our results indicate that the improved IV formulation of HPßCD-HET0016 is effective in inhibiting tumor growth through decreasing proliferation, migration, and neovascularization. Furthermore, HET0016 significantly enhanced sensitivity of TMZ and prolonged survival in PDX GBM. Citation Format: Ali S. Arbab, Meenu Jain, Bhagelu Achyut, Kartik Angara, Mohammad H. Rashid, Asm Iskander, Thaiz F. Borin, Wenbo Zhi, Roxan Ara, Irina Lebedyeva, Hassan Bagher-Ebadian. Magnetic resonance imaging based analysis of tumor growth and vascular parameters in animal model of GBM following IV formulated of HET0016 treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2863. doi:10.1158/1538-7445.AM2017-2863