OKlahoma Nitrone-007: novel treatment for diffuse intrinsic pontine glioma

Journal of Translational Medicine

Nataliya Smith¹  Debra Saunders¹  Rheal A. Towner²  Michelle Zalles³  Rafal Gulej⁴  Lincy Thomas⁵  Kar-Ming Fung⁶  Angel M. Carcaboso⁷  Megan Lerner⁸ 

[1] Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, 73104, Oklahoma City, OK, USA;Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, 73104, Oklahoma City, OK, USA;Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, 73104, Oklahoma City, OK, USA;Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, 73104, Oklahoma City, OK, USA;Pharmaceutical Department, Medical University of Lodz, Lodz, Poland;Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th Street, 73104, Oklahoma City, OK, USA;The Jimmy Everest Center for Cancer and Blood Disorders in Children, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;University of Texas Southwestern in the Division of Hematology and Oncology, Dallas, TX, USA;Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;Department of Pediatric Hematology and Oncology, Hospital Sant Juan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona, Spain;Surgery Research Laboratory, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;

关键词: Diffuse intrinsic pontine glioma (DIPG);    ACVR1 mutation;    Patient-derived xenograft (PDX);    OKN-007;    Magnetic resonance imaging (MRI);    Diffusion-weighted imaging (DWI);    Microvessel density (MVD);    Apoptosis;    H3K27 trimethylation;   

DOI  :  10.1186/s12967-020-02593-5

来源: Springer

【 摘 要 】

BackgroundDiffuse intrinsic pontine glioma (DIPG) is the most common brainstem cancer in childhood. This rapidly progressing brainstem glioma holds a very dismal prognosis with median survival of less than 1 year. Despite extensive research, no significant therapeutic advancements have been made to improve overall survival in DIPG patients.MethodsHere, we used an orthotopic xenograft pediatric DIPG (HSJD-DIPG-007) mouse model to monitor the effects of anti-cancer agent, OKlahoma Nitrone-007 (OKN-007), as an inhibitor of tumor growth after 28 days of treatment. Using magnetic resonance imaging (MRI), we confirmed the previously described efficacy of LDN-193189, a known activin A receptor, type I (ACVR1) inhibitor, in decreasing tumor burden and found that OKN-007 was equally efficacious.ResultsAfter 28 days of treatment, the tumor volumes were significantly decreased in OKN-007 treated mice (p < 0.01). The apparent diffusion coefficient (ADC), as a measure of tissue structural alterations, was significantly decreased in OKN-007 treated tumor-bearing mice (p < 0.0001). Histological analysis also showed a significant decrease in CD34 expression, essential for angiogenesis, of OKN-007 treated mice (p < 0.05) compared to LDN-193189 treated mice. OKN-007-treated mice also significantly decreased protein expression of the human nuclear antigen (HNA) (p < 0.001), ACVR1 (p < 0.0001), and c-MET (p < 0.05), as well as significantly increased expression of cleaved caspase 3 (p < 0.001) and histone H3 K27-trimethylation (p < 0.01), compared to untreated mouse tumors.ConclusionsWith the dismal prognosis and limited effective chemotherapy available for DIPG, there is significant room for continued research studies, and OKN-007 merits further exploration as a therapeutic agent.

【 授权许可】

CC BY