https://scholar.dgist.ac.kr/handle/20.500.11750/16014 2026-04-04T12:10:15Z 2026-04-04T12:10:15Z 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 Park, Jiyoon Chung, Chan https://scholar.dgist.ac.kr/handle/20.500.11750/47709 2025-08-12T09:10:33Z 2023-03-31T15:00:00Z

Title: Epigenetic and Metabolic Changes in Diffuse Intrinsic Pontine Glioma Author(s): Park, Jiyoon; Chung, Chan Abstract: Diffuse midline glioma (DMG), hitherto known as diffuse intrinsic pontine glioma (DIPG), is a rare and aggressive form of brain cancer that primarily affects children. Although the exact cause of DMG/DIPG is not known, a large proportion of DMG/DIPG tumors harbor mutations in the gene encoding the histone H3 protein, specifically the H3K27M mutation. This mutation decreases the level of H3K27me3, a histone modification that plays a vital role in regulating gene expression through epigenetic regulation. The mutation also alters the function of polycomb repressive complex 2 (PRC2), thereby preventing the repression of genes associated with cancer development. The decrease in H3K27me3 caused by the histone H3 mutation is accompanied by an increase in the level of H3K27ac, a post-translational modification related to active transcription. Dysregulation of histone modification markedly affects gene expression, contributing to cancer development and progression by promoting uncontrolled cell proliferation, tumor growth, and metabolism. DMG/DIPG alters the metabolism of methionine and the tricarboxylic acid cycle, as well as glucose and glutamine uptake. The role of epigenetic and metabolic changes in the development of DMG/DIPG has been studied extensively, and understanding these changes is critical to developing therapies targeting these pathways. Studies are currently underway to identify new therapeutic targets for DMG/DIPG, which may lead to the development of effective treatments for this devastating disease. © 2023 The Korean Brain Tumor Society, The Korean Society for NeuroOncology, and The Korean Society for Pediatric Neuro-Oncology

2023-03-31T15:00:00Z