title: 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 cancer-related 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.
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America; Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Coutinho de Souza
authors.affiliation: University of Oklahoma Children's Hospital, Oklahoma City, OK, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: Mallory
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Smith
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America.
authors.forename: Debra
authors.initials: D
authors.lastname: Saunders
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX, United States of America.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.affiliation: University of Oklahoma Children's Hospital, Oklahoma City, OK, United States of America.
authors.forename: Rene Y
authors.initials: RY
authors.lastname: McNall-Knapp
authors.affiliation: Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, United States of America; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Department of Pathology, Oklahoma City Veterans Affairs Medical Center, Oklahoma City, OK, United States of America.
authors.forename: Kar-Ming
authors.initials: KM
authors.lastname: Fung
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States of America; Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, United States of America; Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK, United States of America.
authors.forename: Rheal A
authors.initials: RA
authors.lastname: Towner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D001557:Benzenesulfonates / Q000627:therapeutic use* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D058575:Decorin / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007097:Imines / Q000627:therapeutic use* / Q000633:toxicity; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013429:Sulfatases / Q000378:metabolism; D015996:Survival Rate; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D058575:Decorin; D007097:Imines; C552724:OKN 007; D020796:Receptor, Platelet-Derived Growth Factor alpha; C514911:Sulf2 protein, mouse; D013429:Sulfatases