title: Vamorolone, a dissociative steroidal compound, reduces pro-inflammatory cytokine expression in glioma cells and increases activity and survival in a murine model of cortical tumor.
abstract: Corticosteroids, such as dexamethasone, are routinely used as palliative care in neuro-oncology for their anti-inflammatory benefits, however many patients experience dose limiting side effects caused by glucocorticoid response element (GRE)-mediated transcription. The purpose of this study was to use a murine model to investigate a new steroid alternative, vamorolone, which promises to reduce side effects through dissociating GRE-mediated transcription and NF-κB -mediated anti-inflammatory actions. To compare vamorolone to dexamethasone in reducing pro-inflammatory signals in vitro, murine glioma cells were treated with dexamethasone, vamorolone or vehicle control. Changes in mRNA expression were assessed using the nanostring inflammatory platform. Furthermore, drug efficacy, post-treatment behavioral activity and side effects were assessed by treating two cohorts of brain tumor bearing mice with dexamethasone, vamorolone, or vehicle control. Our investigation showed that treatment with vamorolone resulted in a reduction of pro-inflammatory signals in tumor cells in vitro similar to treatment with dexamethasone. Treatment with vamorolone resulted in a better safety profile in comparison to dexamethasone treatment. Vamorolone- treated mice showed similar or better activity and survival when compared to dexamethasone-treated mice. Our data indicate vamorolone is a potential steroid-sparing alternative for treating patients with brain tumors.
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.|Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wells
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Kambhampati
authors.affiliation: ReveraGen BioPharma, Rockville, MD, USA.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Damsker
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Yadavilli
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Jamila
authors.initials: J
authors.lastname: Gittens
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Mojca
authors.initials: M
authors.lastname: Stampar
authors.affiliation: Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.affiliation: Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Nazarian
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology* / Q000633:toxicity; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D013256:Steroids; D003907:Dexamethasone
keywords: anti-inflammatory; cytokines; glucocorticoids; pediatric brain tumors; pre-clinical testing