https://scholar.dgist.ac.kr/handle/20.500.11750/16013 2026-04-04T12:10:41Z https://scholar.dgist.ac.kr/handle/20.500.11750/60063 Title: Lactate metabolism in H3K27M mutant diffuse midline gliomas Author(s): Lum, Joanna; Deogharkar, Akash; Chung, Chan; Sajjakulnukit, Peter; Lyssiotis, Costas; Venneti, Sriram Abstract: Metabolic reprogramming driven by oncogenes is a cancer hallmark that enables tumor cells to consume nutrients in vast quantities to support their unchecked proliferation. Our laboratory has shown that the H3K27M mutation in Diffuse Midline Glioma (DMG), driven by the Warburg effect, enhances glycolysis and promotes lactate production. Historically/conventionally, lactate was thought to be a metabolic waste product. However, recent studies have challenged this notion by demonstrating numerous biological roles for lactate in various disease settings. This includes the acidification of the tumor microenvironment, immune suppression, and a fuel for mitochondrial energy production. These discoveries have prompted our efforts to investigate the role of lactate metabolism in DMG. Despite its recognized roles in other cancer types, lactate’s contribution to DMG biology is not well characterized. This study explores its energetic utilization by DMG cells. Using liquid chromatography/mass spectrometry (LC/MS) in isogenic mouse neuronal stem cells, we find that H3K27M, compared to H3 WT cells, have elevated intracellular lactate levels. Furthermore, patient-derived DMG cells utilize lactate as an energy source in nutrient-depleted conditions. Notably, genetic and pharmacologic inhibition of lactate dehydrogenase (LDHA & LDHB) hinders cell growth. These findings suggest that lactate metabolism plays a critical role in the physiology of DMG cells and warrant further investigation into its potential role in driving DMG cancer progression. 2025-11-18T15:00:00Z https://scholar.dgist.ac.kr/handle/20.500.11750/57239 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 https://scholar.dgist.ac.kr/handle/20.500.11750/47761 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 https://scholar.dgist.ac.kr/handle/20.500.11750/47710 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