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We are analyzing https://www.biorxiv.org/content/10.1101/2024.06.06.597703v2.

Title:
Chromatin remodeling with combined FACT and BET inhibition disrupts oncogenic transcription in Diffuse Midline Glioma | bioRxiv
Description:
Aberrant epigenetic regulation is a hallmark of Diffuse Midline Glioma (DMG), an incurable pediatric brain tumor. The H3K27M driver histone mutation leads to transcriptional dysregulation, indicating that targeting the epigenome and transcription may be key therapeutic strategies against this highly aggressive cancer. One such target is the Facilitates Chromatin Transcription (FACT) histone chaperone. We found FACT to be enriched at developmental gene promoters, coinciding with regions of open chromatin and binding motifs of core DMG regulatory transcription factors. Furthermore, FACT interacted and co-localized with the Bromodomain and Extra-Terminal Domain (BET) protein BRD4 at promoters and enhancers, suggesting functional cooperation between FACT and BRD4 in DMG. In vitro , a combinatorial therapeutic approach using the FACT inhibitor CBL0137, coupled with BET inhibition revealed potent and synergistic cytotoxicity across a range of DMG cultures. These results were recapitulated in vivo , significantly extending survival in three independent orthotopic PDX models of DMG. Mechanistically, we show that CBL0137 treatment decreased chromatin accessibility, synergizing with BET inhibition to cause broad transcriptional collapse, silencing several key oncogenes including MYC, PDGFRA , MDM4 and SOX2 , as well as causing alterations to the splicing landscape. Notably, this combination also elicited immune-related effects, including activation of the interferon response and antigen presentation mechanisms in DMG cells and induction of an activated state in macrophages and T cells, as demonstrated in an immunocompetent setting with spatial transcriptomics. Altogether, our data highlights the therapeutic promise of simultaneously targeting FACT and BET proteins in DMG, offering a dual tumor-intrinsic and immune-mediated strategy for combating this devastating pediatric brain tumor. ### Competing Interest Statement DSZ declares consulting/advisory board fees from Bayer, Astra Zeneca, Accendatech, Novartis, Day One, FivePhusion, Amgen, Alexion, and Norgine and research support from Accendatech. The remaining authors have declared that no competing interests exist. Cancer Institute of New South Wales, https://ror.org/029a54f25, 2022/ECF1425, 2019/TPG2037 National Health and Medical Research Council, https://ror.org/011kf5r70, 2019056, GNT2017898 Kids
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💥 Very Strong Traffic: 200k - 500k visitors per month


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Keywords {🔍}

view, orcid, profile, biology, fact, dmg, cancer, bet, chromatin, transcription, medrxiv, subject, reviews, clinical, results, preprint, inhibition, therapeutic, research, institute, project, foundation, biorxiv, university, trials, epidemiology, search, diffuse, midline, glioma, david, robert, pdf, pediatric, brain, tumor, histone, transcriptional, targeting, key, developmental, promoters, brd, cbl, including, cells, competing, accendatech, support, authors,

Topics {✒️}

epidemiology subject categories developmental gene promoters clinical trials diffuse midline glioma highly aggressive cancer elicited immune-related effects biorxiv subject category genetics microbiology reviews epidemiology papers competing interests exist author/funder 2019/tpg2037 national health health-related information keyword advanced search facilitates chromatin transcription dual tumor-intrinsic project cure starts immune-mediated strategy key therapeutic strategies extra-terminal domain suggesting functional cooperation fact inhibitor cbl0137 significantly extending survival antigen presentation mechanisms medical research council chan zuckerberg initiative imperial college london vrije universiteit amsterdam articles animal behavior combinatorial therapeutic approach connie foundation levi broad transcriptional collapse generous financial support context preprint chromatin remodeling org/04edq9h05 copyright simultaneously targeting fact bet inhibition histone chaperone research support open chromatin including activation california institute massachusetts institute bet proteins therapeutic promise transcriptional dysregulation copyright holder

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