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, Madhuri Kambhampati, Jesse M Damsker, Heather Gordish-Dressman, Sridevi Yadavilli, Oren J Becher, Jamila Gittens, Mojca Stampar, Roger J Packer, Javad Nazarian, Elizabeth Wells, Madhuri Kambhampati, Jesse M Damsker, Heather Gordish-Dressman, Sridevi Yadavilli, Oren J Becher, Jamila Gittens, Mojca Stampar, Roger J Packer, Javad Nazarian

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.

Keywords: anti-inflammatory; cytokines; glucocorticoids; pediatric brain tumors; pre-clinical testing.

Conflict of interest statement

CONFLICTS OF INTEREST

None declared by Drs. Wells, Dressman-Gordish, Yadavilli, Becher, Packer, Nazarian, Ms. Kambhampati, Gittens, and Stampar.

Dr. Damsker is employed by ReveraGen BioPharma Inc. and has stock options.

Figures

Figure 1. Vamorolone does not inhibit the…
Figure 1. Vamorolone does not inhibit the growth of mice in vivo
Tumor bearing mice were treated with vehicle (cherry syrup, control), dexamethasone and vamorolone and mice body length (A) and tibia length (B) were measured at the endpoint. Dexamethasone treatment significantly reduces the growth of tumor bearing mice as measured at the endpoint (A) Dexamethasone also decreased the bone growth as assessed by tibia measures (B) vamorolone displayed significant measures close to the vehicle treatment. One-way Anova, *p < 0.05, **p < 0.01, ***p < 0.001.
Figure 2. Vamorolone is less immunotoxic compared…
Figure 2. Vamorolone is less immunotoxic compared to dexamethasone
Mice were treated with vehicle, dexamethasone or vamorolone and spleen was analyzed for size and weight. Dexamethasone significantly reduced the spleen size (A) and weight (B) in tumor bearing mice compared to vamorolone or untreated mice. However, mice treated with dexamethasone showed significantly smaller spleen when compared to vamorolone or vehicle- treated mice. One-way Anova, **p < 0.01, ***p < 0.001.
Figure 3. Vamorolone and dexamethasone increase the…
Figure 3. Vamorolone and dexamethasone increase the activity of tumor bearing mice
Mice injected with glioma cells (PKC-L) were imaged for signs of tumor formation (A) Tumor breading mice were treated with dexamethasone, vamorolone or control vehicle and horizontal activity was measured using VersaMax open field activity monitoring system at both pre and post-treatment time points (B) Although a significant decrease in activity was observed from pre-treatment to post-treatment, mice treated with vamorolone showed an increased activity when compared with vehicle-treated mice.
Figure 4. Tumor bearing mice when treated…
Figure 4. Tumor bearing mice when treated with vamorolone have better survival
Tumor bearing mice treated with vamorolone survive longer. Kaplan-Meier plot analysis showed that the vamorolone treated mice show a significantly (p = 0.025) increased survival time over those treated with dexamethasone or vehicle control (A) Necropsy analysis of brain harvested from these mice showed hypercellularity and proliferative tumors as shown by H&E and Ki67 respectively, 20X magnification (B).

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Source: PubMed

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