Summary of Study ST001838
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001160. The data can be accessed directly via it's Project DOI: 10.21228/M8RT34 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST001838 |
| Study Title | Reversing Epigenetic Gene Silencing to Overcome Immune Evasion in CNS Malignancies |
| Study Summary | Glioblastoma is an aggressive brain malignancy with a dismal prognosis. With emerging evidence that disproves the immune privileged environment in the brain, there is much interest in examining various immunotherapy strategies to treat these incurable cancers. Unfortunately, to date, clinical studies investigating immunotherapy regimens have not provided much evidence of efficacy, leading to questions about the suitability of immunotherapy strategies for these tumors. Inadequate inherent populations of lymphocytes in tumor (TILs) and limited trafficking of systemic circulating T cells into the central nervous system (CNS) likely contribute to the poor response to immunotherapy treatment for primary CNS cancers. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier permeable small molecule inhibitor of EZH2, to reverse the epigenetic silencing of chemokines like CXCL9 and CXCL10. When combined with anti-PD-1 treatment, these IFN driven chemokines promote T cell infiltration, resulting in decreased tumor growth and enhanced survival in immunocompetent murine sub-cutaneous and intracranial tumor syngeneic models of GBM. Examination of the tumor micro-environment revealed that the decrease in tumor growth in the mice treated with the drug combination was accompanied by increased tumor CD8 T cell infiltration along with higher IFN expression. Additionally, a significant increase in CXCR3+ T cells in the draining lymph nodes was also found. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor. |
| Institute | National Cancer Institute |
| Department | Neuro-Oncology Branch |
| Laboratory | Cancer Metabolism |
| Last Name | Dowdy |
| First Name | Tyrone |
| Address | 37 convent dr, Bldg 37 rm 1142 |
| tyrone.dowdy@nih.gov | |
| Phone | 2407607066 |
| Submit Date | 2021-06-11 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | d |
| Analysis Type Detail | LC-MS |
| Release Date | 2021-06-30 |
| Release Version | 1 |
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Sample Preparation:
| Sampleprep ID: | SP001921 |
| Sampleprep Summary: | Serum (50 µL) was transferred to 200 μL ice-chilled (4°C) MilliQ H2O. Tissue (~16 mg) was measured from subcutaneous and intracranial samples followed by addition of 250 μL MilliQ H2O. Then, samples were sonicated at 40 amps (~30 s) until homogeneous. 80 μL of at 0.150 µg/mL debrisoquine in 60% methanol (MeOH)/40% water(aq) reagent was added. 500 μL chilled (-20°C) MeOH was added, vortexed (med) and incubated 15 min on ice. 250 μL chilled (-20°C) Chloroform was added, vortexed (high) and incubated 20 min in ice on rotating mixer. Mixture was centrifuged (13,000x g) for 18 min at 4°C. 705 μL of hydrophilic upper layer was aspirated and transferred to separate 1.5 mL microtubes, dried to completion under N2 gas sample concentrator, and stored at -80°C |
| Sampleprep Protocol ID: | Extraction |
| Processing Storage Conditions: | -80℃ |
| Extraction Method: | LCMS Extraction |
| Extract Cleanup: | Bligh-Dyer biphasic separation, discard protein disk and dried to completion under N2 gas |
| Sample Resuspension: | 80 uL 60% MeOH (aq) |
| Sample Spiking: | Internal standard 0.150 µg/mL debrisoquine(IS) was added to each |
