https://scholar.dgist.ac.kr/handle/20.500.11750/16014 2026-05-15T00:39:03Z 2026-05-15T00:39:03Z Park, Jiyoon Jeon, Jinha Gim, Sujeong Chung, Chan https://scholar.dgist.ac.kr/handle/20.500.11750/60354 2026-05-12T00:40:13Z

Title: Histone mark remodeling in cancer: an enhancer-centered perspective Author(s): Park, Jiyoon; Jeon, Jinha; Gim, Sujeong; Chung, Chan Abstract: Epigenetic deregulation is a defining feature of cancer, and histone modification remodeling plays a central role in reshaping malignant transcriptional programs. Histone marks collectively organize chromatin states that govern enhancer activity, promoter competence, and stability of repressive domains. Across diverse tumor types, redistribution of active and repressive histone modifications reconfigures regulatory landscapes that sustain oncogenic amplification, lineage plasticity, and adaptive resistance. In this review, we examine histone mark remodeling in cancer through an enhancer-centered perspective. We discuss how the gain of H3K27ac-marked enhancers, super-enhancer formation, the erosion of lineage-restrictive regulatory elements, and the redistribution of repressive marks cooperate to reorganize transcriptional circuitry. We further outline the convergent mechanisms driving these alterations, including mutations in chromatin regulators, signal-dependent modulation of epigenetic enzymes, metabolic influences on chromatin state, and changes in three-dimensional genome architecture. The functional consequences of histone mark reprogramming, ranging from cell state transitions and tumor heterogeneity to transcriptional dependency and therapy-associated chromatin adaptation, are considered in the context of tumor evolution. Finally, we highlight emerging single-cell, spatial, and integrative multi-omics approaches that enable systems-level interpretation of chromatin landscapes and identification of context-specific vulnerabilities. By framing histone modification dynamics in terms of enhancer reconfiguration, this review provides a mechanistic and translational perspective on how chromatin remodeling sustains malignant identity and offers opportunities for therapeutic intervention.

Mbah, Nneka E. Myers, Amy L. Sajjakulnukit, Peter Chung, Chan Thompson, Joyce K. Hong, Hanna S. Giza, Heather Dang, Derek Nwosu, Zeribe C. Shan, Mengrou Sweha, Stefan R. Maydan, Daniella D. Chen, Brandon Zhang, Li Magnuson, Brian Zhu, Zirui Radyk, Megan Lavoie, Brooke Yadav, Viveka Nand Koo, Imhoi Patterson, Andrew D. Wahl, Daniel R. Franchi, Luigi Agnihotri, Sameer Koschmann, Carl J. Venneti, Sriram Lyssiotis, Costas A. https://scholar.dgist.ac.kr/handle/20.500.11750/57239 2025-07-25T02:42:26Z 2024-09-30T15:00:00Z

Title: Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma Author(s): Mbah, Nneka E.; Myers, Amy L.; Sajjakulnukit, Peter; Chung, Chan; Thompson, Joyce K.; Hong, Hanna S.; Giza, Heather; Dang, Derek; Nwosu, Zeribe C.; Shan, Mengrou; Sweha, Stefan R.; Maydan, Daniella D.; Chen, Brandon; Zhang, Li; Magnuson, Brian; Zhu, Zirui; Radyk, Megan; Lavoie, Brooke; Yadav, Viveka Nand; Koo, Imhoi; Patterson, Andrew D.; Wahl, Daniel R.; Franchi, Luigi; Agnihotri, Sameer; Koschmann, Carl J.; Venneti, Sriram; Lyssiotis, Costas A. Abstract: H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain. © The Author(s) 2024.

2024-09-30T15:00:00Z Venneti, Sriram Kawakibi, Abed Rahman Ji, Sunjong Waszak, Sebastian M. Sweha, Stefan R. Mota, Mateus Pun, Matthew Deogharkar, Akash Chung, Chan Tarapore, Rohinton S. Ramage, Samuel Chi, Andrew Wen, Patrick Y. Arrillaga-Romany, Isabel Batchelor, Tracy T. Butowski, Nicholas A. Sumrall, Ashley Shonka, Nicole Harrison, Rebecca A. de Groot, John Mehta, Minesh Hall, Matthew D. Daghistani, Doured Cloughesy, Timothy F. Ellingson, Benjamin M. Beccaria, Kevin Varlet, Pascale Kim, Michelle M. Umemura, Yoshie Garton, Hugh Franson, Andrea Schwartz, Jonathan Jain, Rajan Kachman, Maureen Baum, Heidi Burant, Charles F. Mottl, Sophie L. Cartaxo, Rodrigo T. John, Vishal Messinger, Dana Qin, Tingting Peterson, Erik Sajjakulnukit, Peter Ravi, Karthik Waugh, Alyssa Walling, Dustin Ding, Yujie Xia, Ziyun Schwendeman, Anna Hawes, Debra Yang, Fusheng Judkins, Alexander R. Wahl, Daniel Lyssiotis, Costas A. de la Nava, Daniel Alonso, Marta M. Eze, Augustine Spitzer, Jasper Schmidt, Susanne V. Duchatel, Ryan J. Dun, Matthew D. Cain, Jason E. Jiang, Li Stopka, Sylwia A. Baquer, Gerard Regan, Michael S. Filbin, Mariella G. Agar, Nathalie Y. R. Zhao, Lili Kumar-Sinha, Chandan Mody, Rajen Chinnaiyan, Arul Kurokawa, Ryo Pratt, Drew Yadav, Viveka N. Grill, Jacques Kline, Cassie Mueller, Sabine Resnick, Adam Nazarian, Javad Allen, Joshua E. Odia, Yazmin Gardner, Sharon L. Koschmann, Carl https://scholar.dgist.ac.kr/handle/20.500.11750/47761 2025-07-25T03:38:50Z 2023-10-31T15:00:00Z

Title: Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways Author(s): Venneti, Sriram; Kawakibi, Abed Rahman; Ji, Sunjong; Waszak, Sebastian M.; Sweha, Stefan R.; Mota, Mateus; Pun, Matthew; Deogharkar, Akash; Chung, Chan; Tarapore, Rohinton S.; Ramage, Samuel; Chi, Andrew; Wen, Patrick Y.; Arrillaga-Romany, Isabel; Batchelor, Tracy T.; Butowski, Nicholas A.; Sumrall, Ashley; Shonka, Nicole; Harrison, Rebecca A.; de Groot, John; Mehta, Minesh; Hall, Matthew D.; Daghistani, Doured; Cloughesy, Timothy F.; Ellingson, Benjamin M.; Beccaria, Kevin; Varlet, Pascale; Kim, Michelle M.; Umemura, Yoshie; Garton, Hugh; Franson, Andrea; Schwartz, Jonathan; Jain, Rajan; Kachman, Maureen; Baum, Heidi; Burant, Charles F.; Mottl, Sophie L.; Cartaxo, Rodrigo T.; John, Vishal; Messinger, Dana; Qin, Tingting; Peterson, Erik; Sajjakulnukit, Peter; Ravi, Karthik; Waugh, Alyssa; Walling, Dustin; Ding, Yujie; Xia, Ziyun; Schwendeman, Anna; Hawes, Debra; Yang, Fusheng; Judkins, Alexander R.; Wahl, Daniel; Lyssiotis, Costas A.; de la Nava, Daniel; Alonso, Marta M.; Eze, Augustine; Spitzer, Jasper; Schmidt, Susanne V.; Duchatel, Ryan J.; Dun, Matthew D.; Cain, Jason E.; Jiang, Li; Stopka, Sylwia A.; Baquer, Gerard; Regan, Michael S.; Filbin, Mariella G.; Agar, Nathalie Y. R.; Zhao, Lili; Kumar-Sinha, Chandan; Mody, Rajen; Chinnaiyan, Arul; Kurokawa, Ryo; Pratt, Drew; Yadav, Viveka N.; Grill, Jacques; Kline, Cassie; Mueller, Sabine; Resnick, Adam; Nazarian, Javad; Allen, Joshua E.; Odia, Yazmin; Gardner, Sharon L.; Koschmann, Carl Abstract: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multi-site clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. © 2023 The Authors; Published by the American Association for Cancer Research.

2023-10-31T15:00:00Z Koschmann, Carl Al-Holou, Wajd N. Alonso, Marta M. Anastas, Jamie Bandopadhayay, Pratiti Barron, Tara Becher, Oren Cartaxo, Rodrigo Castro, Maria G. Chung, Chan Clausen, Madison Dang, Derek Doherty, Robert Duchatel, Ryan Dun, Matthew Filbin, Mariella Franson, Andrea Galban, Stefanie Garcia Moure, Marc Garton, Hugh Gowda, Pruthvi Marques, Joana Graca Hawkins, Cynthia Heath, Allison Hulleman, Esther Ji, Sunjong Jones, Chris Kilburn, Lindsay Kline, Cassie Koldobskiy, Michael A. Lim, Daniel Lowenstein, Pedro R. Lu, Q. Richard Lum, Joanna Mack, Stephen Magge, Suresh Marini, Bernard Martin, Donna Marupudi, Neena Messinger, Dana Mody, Rajen Morgan, Meredith Mota, Mateus Muraszko, Karin Mueller, Sabine Natarajan, Siva Kumar Nazarian, Javad Niculcea, Michael Nuechterlein, Nicholas Okada, Hideho Opipari, Valerie Pai, Manjunath P. Pal, Sharmistha Peterson, Erik Phoenix, Timothy Prensner, John R. Pun, Matthew Raju, G. Praveen Reitman, Zachary J. Resnick, Adam Rogawski, David Saratsis, Amanda Sbergio, Stefanie G. Souweidane, Mark Stafford, James M. Tzaridis, Theophilos Venkataraman, Sujatha Vittorio, Orazio Wadden, Jack Wahl, Daniel Wechsler-Reya, Robert J. Yadav, Viveka Nand Zhang, Xu Zhang, Qiang Venneti, Sriram https://scholar.dgist.ac.kr/handle/20.500.11750/47710 2025-07-25T02:45:23Z 2023-12-31T15:00:00Z

Title: A road map for the treatment of pediatric diffuse midline glioma Author(s): Koschmann, Carl; Al-Holou, Wajd N.; Alonso, Marta M.; Anastas, Jamie; Bandopadhayay, Pratiti; Barron, Tara; Becher, Oren; Cartaxo, Rodrigo; Castro, Maria G.; Chung, Chan; Clausen, Madison; Dang, Derek; Doherty, Robert; Duchatel, Ryan; Dun, Matthew; Filbin, Mariella; Franson, Andrea; Galban, Stefanie; Garcia Moure, Marc; Garton, Hugh; Gowda, Pruthvi; Marques, Joana Graca; Hawkins, Cynthia; Heath, Allison; Hulleman, Esther; Ji, Sunjong; Jones, Chris; Kilburn, Lindsay; Kline, Cassie; Koldobskiy, Michael A.; Lim, Daniel; Lowenstein, Pedro R.; Lu, Q. Richard; Lum, Joanna; Mack, Stephen; Magge, Suresh; Marini, Bernard; Martin, Donna; Marupudi, Neena; Messinger, Dana; Mody, Rajen; Morgan, Meredith; Mota, Mateus; Muraszko, Karin; Mueller, Sabine; Natarajan, Siva Kumar; Nazarian, Javad; Niculcea, Michael; Nuechterlein, Nicholas; Okada, Hideho; Opipari, Valerie; Pai, Manjunath P.; Pal, Sharmistha; Peterson, Erik; Phoenix, Timothy; Prensner, John R.; Pun, Matthew; Raju, G. Praveen; Reitman, Zachary J.; Resnick, Adam; Rogawski, David; Saratsis, Amanda; Sbergio, Stefanie G.; Souweidane, Mark; Stafford, James M.; Tzaridis, Theophilos; Venkataraman, Sujatha; Vittorio, Orazio; Wadden, Jack; Wahl, Daniel; Wechsler-Reya, Robert J.; Yadav, Viveka Nand; Zhang, Xu; Zhang, Qiang; Venneti, Sriram Abstract: Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) have shown much promise. We present a consensus roadmap and identify three major barriers: (1) refinement of experimental models to include immune and brain-specific components; (2) collaboration among researchers, clinicians, and industry to integrate patient-derived data through sharing, transparency, and regulatory considerations; and (3) streamlining clinical efforts including biopsy, CNS-drug delivery, endpoint determination, and response monitoring. We highlight the importance of comprehensive collaboration to advance the understanding, diagnostics, and therapeutics for DMGs. © 2023 Elsevier Inc.

2023-12-31T15:00:00Z