Inhibition of Pediatric Glioblastoma Tumor Growth by the Anti-Cancer Agent OKN-007 in Orthotopic Mouse Xenografts

Abstract

Pediatric glioblastomas (pGBM), although rare, are one of the leading causes of cancerrelated deaths in children, with tumors essentially refractory to existing treatments. Here, we describe the use of conventional and advanced in vivo magnetic resonance imaging (MRI) techniques to assess a novel orthotopic xenograft pGBM mouse (IC-3752GBM patient-derived culture) model, and to monitor the effects of the anti-cancer agent OKN-007 as an inhibitor of pGBM tumor growth. Immunohistochemistry support data is also presented for cell proliferation and tumor growth signaling. OKN-007 was found to significantly decrease tumor volumes (p<0.05) and increase animal survival (p<0.05) in all OKN-007-treated mice compared to untreated animals. In a responsive cohort of treated animals, OKN-007 was able to significantly decrease tumor volumes (p<0.0001), increase survival (p<0.001), and increase diffusion (p<0.01) and perfusion rates (p<0.05). OKN-007 also significantly reduced lipid tumor metabolism in responsive animals [(Lip1.3 and Lip0.9)-to-creatine ratio (p<0.05)], as well as significantly decrease tumor cell proliferation (p<0.05) and microvessel density (p<0.05). Furthermore, in relationship to the PDGFRα pathway, OKN-007 was able to significantly decrease SULF2 (p<0.05) and PDGFR-α (platelet-derived growth factor receptor-α) (p<0.05) immunoexpression, and significantly increase decorin expression (p<0.05) in responsive mice. This study indicates that OKN-007 may be an effective anti-cancer agent for some patients with pGBMs by inhibiting cell proliferation and angiogenesis, possibly via the PDGFRα pathway, and could be considered as an additional therapy for pediatric brain tumor patients.

Tumor-targeted Nanoparticle Delivery of HuR siRNA Inhibits Lung Tumor Growth In Vitro and In Vivo By Disrupting the Oncogenic Activity of the RNA-binding Protein HuR

“…Appropriate positive and negative controls were included. The stained tissue sections were analyzed using the Aperio ScanScope Image Analysis System (Aperio, Vista, CA) [36]. HuR and Ki-67 stained tumor tissues were analyzed using a positive nuclear count algorithm with the Aperio ImageScope viewer.…”

Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan

“…The compound designated OK-007, 2,4-disulfophenyl-N-tert-butylnitrone, inhibits the enzymatic activity of Sulf2. This compound was initially explored as a treatment for acute ischemic stroke (262), though has since been investigated as a potential therapeutic for HCC (241) and glioblastoma (242). Coutinho de Souza et al (242) demonstrated the ability for OKN-007 to reduce cell proliferation and the expression of the receptor for platelet derived growth factor, and the authors speculated potential anti-angiogenic properties of OKN-007.…”

ELTD1, an effective anti-angiogenic target for gliomas: preclinical assessment in mouse GL261 and human G55 xenograft glioma models

“…[24][25][26] Treatments GL261 tumor-bearing mice (n = 4-7 per group) were treated with either anti-ELTD1 (ELT, N-20, goat polyclonal [#sc-46951, Santa Cruz Tech]; 2 mg/kg in 100 µL saline every 3 days for up to tumor maximum), anti-VEGF (mouse monoclonal antibody; 1.5-2.0 mg/kg in 100 µL saline every 3 days for up to tumor maximum [Genentech]), or anti-cMet antibodies (c-Met, B-2, mouse monoclonal [#sc-8057, Santa Cruz Tech]; 1 mg/kg in 100 µL saline every 3 days for up to tumor maximum). Untreated mice served as controls for statistical comparison.…”

“…T2-weighted imaging was acquired as previously done by our group. 22,[24][25][26] Tumor volumes were calculated from 3D MRI slices rendered MRI datasets, using Amira v5.6.0 (FEI).…”

“…25,26 Perfusion maps were obtained on a single axial slice of the brain located on the point of the rostro-caudal axis where the tumor had the largest cross section. 25,26 The imaging geometry was a 3.5 × 3.5 mm 2 slice, of 1.5 mm in thickness, with a single shot echo-planar encoding over a 64 × 64 matrix. An echo time of 20 ms and a repetition time of 18 s were used.…”