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

// Elizabeth Wells 1, 2, * , Madhuri Kambhampati 1, * , Jesse M. Damsker 3, * , Heather Gordish-Dressman 1 , Sridevi Yadavilli 1 , Oren J. Becher 4 , Jamila Gittens 1 , Mojca Stampar 1 , Roger J. Packer 2 , Javad Nazarian 1, 5 1 Research Center for Genetic Medicine, Children’s National Health System, Washington, DC, USA 2 Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children’s National Health System, Washington, DC, USA 3 ReveraGen BioPharma, Rockville, MD, USA 4 Duke University Medical Center, Durham, NC, USA 5 Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA * These authors contributed equally to this work Correspondence to: Javad Nazarian, email: JNazarian@ChildrensNational.org Keywords: glucocorticoids, cytokines, anti-inflammatory, pre-clinical testing, pediatric brain tumors Received: November 09, 2016      Accepted: December 13, 2016      Published: December 21, 2016 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.