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1. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.

Author

Sweha, Stefan, Mota, Mateus, Pun, Matthew, Deogharkar, Akash, Chung, Chan, Tarapore, Rohinton, Ramage, Samuel, Chi, Andrew, Wen, Patrick, Arrillaga-Romany, Isabel, Batchelor, Tracy, Butowski, Nicholas, Sumrall, Ashley, Shonka, Nicole, Harrison, Rebecca, de Groot, John, Mehta, Minesh, Hall, Matthew, Daghistani, Doured, Cloughesy, Timothy, Ellingson, Benjamin, Beccaria, Kevin, Varlet, Pascale, Kim, Michelle, Umemura, Yoshie, Garton, Hugh, Franson, Andrea, Schwartz, Jonathan, Jain, Rajan, Kachman, Maureen, Baum, Heidi, Burant, Charles, Mottl, Sophie, Cartaxo, Rodrigo, 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, Wahl, Daniel, Lyssiotis, Costas, de la Nava, Daniel, Alonso, Marta, Eze, Augustine, Spitzer, Jasper, Schmidt, Susanne, Duchatel, Ryan, Dun, Matthew, Cain, Jason, Jiang, Li, Stopka, Sylwia, Baquer, Gerard, Regan, Michael, Filbin, Mariella, Agar, Nathalie, Zhao, Lili, Kumar-Sinha, Chandan, Mody, Rajen, Chinnaiyan, Arul, Kurokawa, Ryo, Pratt, Drew, Yadav, Viveka, Grill, Jacques, Kline, Cassie, Venneti, Sriram, Kawakibi, Abed, Ji, Sunjong, Resnick, Adam, Nazarian, Javad, Allen, Joshua, Odia, Yazmin, Gardner, Sharon, Koschmann, Carl, Mueller, Sabine, and Waszak, Sebastian

Subjects
Humans, Glioma, Brain Neoplasms, Histones, Treatment Outcome, Epigenesis, Genetic, Mutation
Abstract

UNLABELLED: 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 multisite 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. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Published
2023

2. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma

Author

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, and Lyssiotis, Costas A.

Published
2024
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3. Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma

Author

Peterson, Erik R., Sajjakulnukit, Peter, Scott, Andrew J., Heaslip, Caleb, Andren, Anthony, Wilder-Romans, Kari, Zhou, Weihua, Palavalasa, Sravya, Korimerla, Navyateja, Lin, Angelica, O’Brien, Alexandra, Kothari, Ayesha, Zhao, Zitong, Zhang, Li, Morgan, Meredith A., Venneti, Sriram, Koschmann, Carl, Jabado, Nada, Lyssiotis, Costas A., Castro, Maria G., and Wahl, Daniel R.

Published
2024
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4. Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma.

Author

Messinger, Dana, Harris, Micah, Cummings, Jessica, Thomas, Chase, Yang, Tao, Sweha, Stefan, Woo, Rinette, Siddaway, Robert, Burkert, Martin, Stallard, Stefanie, Qin, Tingting, Mullan, Brendan, Siada, Ruby, Ravindran, Ramya, Niculcea, Michael, Dowling, Abigail, Bradin, Joshua, Ginn, Kevin, Gener, Melissa, Dorris, Kathleen, Vitanza, Nicholas, Schmidt, Susanne, Spitzer, Jasper, Li, Jiang, Filbin, Mariella, Cao, Xuhong, Castro, Maria, Lowenstein, Pedro, Mody, Rajen, Chinnaiyan, Arul, Desprez, Pierre-Yves, McAllister, Sean, Dun, Matthew, Hawkins, Cynthia, Waszak, Sebastian, Venneti, Sriram, Koschmann, Carl, and Yadav, Viveka

Subjects
CBD, DMG, ID1, ROS, invasion/migration, Animals, Humans, Mice, Brain, Brain Neoplasms, Calcium-Binding Proteins, Extracellular Matrix Proteins, Glioma, Histones, Inhibitor of Differentiation Protein 1, Mutation, Signal Transduction
Abstract

BACKGROUND: Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. METHODS: Whole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected. RESULTS: Increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial. CONCLUSIONS: H3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.

Published
2023

6. Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas

Author

Panwalkar, Pooja, Tamrazi, Benita, Dang, Derek, Chung, Chan, Sweha, Stefan, Natarajan, Siva Kumar, Pun, Matthew, Bayliss, Jill, Ogrodzinski, Martin P, Pratt, Drew, Mullan, Brendan, Hawes, Debra, Yang, Fusheng, Lu, Chao, Sabari, Benjamin R, Achreja, Abhinav, Heon, Jin, Animasahun, Olamide, Cieslik, Marcin, Dunham, Christopher, Yip, Stephen, Hukin, Juliette, Phillips, Joanna J, Bornhorst, Miriam, Griesinger, Andrea M, Donson, Andrew M, Foreman, Nicholas K, Garton, Hugh JL, Heth, Jason, Muraszko, Karin, Nazarian, Javad, Koschmann, Carl, Jiang, Li, Filbin, Mariella G, Nagrath, Deepak, Kool, Marcel, Korshunov, Andrey, Pfister, Stefan M, Gilbertson, Richard J, Allis, C David, Chinnaiyan, Arul M, Lunt, Sophia Y, Blüml, Stefan, Judkins, Alexander R, and Venneti, Sriram

Subjects
Cancer, Biotechnology, Genetics, Rare Diseases, Orphan Drug, Neurosciences, Brain Disorders, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Child, Ependymoma, Epigenesis, Genetic, Epigenomics, Histones, Humans, Metabolic Networks and Pathways, Mice, Biological Sciences, Medical and Health Sciences
Abstract

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Published
2021

7. An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma

Author

Casillo, Stephanie M., Gatesman, Taylor A., Chilukuri, Akanksha, Varadharajan, Srinidhi, Johnson, Brenden J., David Premkumar, Daniel R., Jane, Esther P., Plute, Tritan J., Koncar, Robert F., Stanton, Ann-Catherine J., Biagi-Junior, Carlos A.O., Barber, Callie S., Halbert, Matthew E., Golbourn, Brian J., Halligan, Katharine, Cruz, Andrea F., Mansi, Neveen M., Cheney, Allison, Mullett, Steven J., Land, Clinton Van’t, Perez, Jennifer L., Myers, Max I., Agrawal, Nishant, Michel, Joshua J., Chang, Yue-Fang, Vaske, Olena M., MichaelRaj, Antony, Lieberman, Frank S., Felker, James, Shiva, Sruti, Bertrand, Kelsey C., Amankulor, Nduka, Hadjipanayis, Costas G., Abdullah, Kalil G., Zinn, Pascal O., Friedlander, Robert M., Abel, Taylor J., Nazarian, Javad, Venneti, Sriram, Filbin, Mariella G., Gelhaus, Stacy L., Mack, Stephen C., Pollack, Ian F., and Agnihotri, Sameer

Published
2024
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8. Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome

Author

Panwalkar, Pooja, Clark, Jonathan, Ramaswamy, Vijay, Hawes, Debra, Yang, Fusheng, Dunham, Christopher, Yip, Stephen, Hukin, Juliette, Sun, Yilun, Schipper, Matthew J, Chavez, Lukas, Margol, Ashley, Pekmezci, Melike, Chung, Chan, Banda, Adam, Bayliss, Jill M, Curry, Sarah J, Santi, Mariarita, Rodriguez, Fausto J, Snuderl, Matija, Karajannis, Matthias A, Saratsis, Amanda M, Horbinski, Craig M, Carret, Anne-Sophie, Wilson, Beverly, Johnston, Donna, Lafay-Cousin, Lucie, Zelcer, Shayna, Eisenstat, David, Silva, Marianna, Scheinemann, Katrin, Jabado, Nada, McNeely, P Daniel, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Hawkins, Cynthia, Korshunov, Andrey, Judkins, Alexander R, and Venneti, Sriram

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Genetics, Brain Cancer, Rare Diseases, Neurosciences, Clinical Research, Pediatric Cancer, Cancer, Clinical Trials and Supportive Activities, Pediatric, Child, Child, Preschool, Disease-Free Survival, Ependymoma, Female, Humans, Infant, Infratentorial Neoplasms, Jumonji Domain-Containing Histone Demethylases, Male, Prognosis, Registries, Survival Rate, Childhood ependymoma, Epigenetics, H3K27me3, Molecular subgrouping, Neurology & Neurosurgery
Abstract

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n = 72) and EPN_PFB tumors (n = 40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n = 133 and n = 97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.

Published
2017

9. Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas

Author

Bayliss, Jill, Mukherjee, Piali, Lu, Chao, Jain, Siddhant U, Chung, Chan, Martinez, Daniel, Sabari, Benjamin, Margol, Ashley S, Panwalkar, Pooja, Parolia, Abhijit, Pekmezci, Melike, McEachin, Richard C, Cieslik, Marcin, Tamrazi, Benita, Garcia, Benjamin A, La Rocca, Gaspare, Santi, Mariarita, Lewis, Peter W, Hawkins, Cynthia, Melnick, Ari, Allis, C David, Thompson, Craig B, Chinnaiyan, Arul M, Judkins, Alexander R, and Venneti, Sriram

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Brain Disorders, Pediatric, Neurosciences, Human Genome, Rare Diseases, Cancer, Pediatric Cancer, Brain Cancer, Genetics, Brain Neoplasms, Central Nervous System, Child, CpG Islands, DNA Methylation, Ependymoma, Epigenesis, Genetic, Gene Expression Profiling, Genome, Human, Histones, Humans, Mutation, Prognosis, Treatment Outcome, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) hypermethylation [PF group A (PFA)], implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas. PF-ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF-ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF-ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas.

Published
2016

11. Everolimus improves the efficacy of dasatinib in PDGFR[alpha]-driven glioma

Author

Miklja, Zachary, Yadav, Viveka Nand, Cartaxo, Rodrigo T., Siada, Ruby, Thomas, Chase C., Cummings, Jessica R., Mullan, Brendan, Stallard, Stefanie, Paul, Alyssa, Bruzek, Amy K., Wierzbicki, Kyle, Yang, Tao, Garcia, Taylor, Wolfe, Ian, Leonard, Marcia, Robertson, Patricia L., Garton, Hugh J.L., Wahl, Daniel R., Parmar, Hemant, Sarkaria, Jann N., Kline, Cassie, Mueller, Sabine, Nicolaides, Theodore, Glasser, Chana, Leary, Sarah E.S., Venneti, Sriram, Kumar-Sinha, Chandan, Chinnaiyan, Arul M., Mody, Rajen, Pai, Manjunath P., Phoenix, Timothy N., Marini, Bernard L., and Koschmann, Carl

Subjects
Gliomas -- Drug therapy, Tumor proteins -- Drug therapy, Child health, Lenvatinib, Antineoplastic agents, Health care industry
Abstract

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFR[alpha] alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFR[alpha]-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFR[alpha]-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFR[alpha] alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor-bearing mice (mutant TP53, mutant PDGFR[alpha], H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFR[alpha]-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population., Introduction High-grade gliomas (HGGs) are common and aggressive pediatric and adult brain tumors. The median overall survival (OS) of adult patients diagnosed with glioblastoma (GBM), grade IV glioma, is 12.6 [...]

Published
2020
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12. TMET-02. CLINICAL EFFICACY OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS IS DRIVEN BY DISRUPTION OF INTEGRATED METABOLIC AND EPIGENETIC PATHWAYS

Author

Venneti, Sriram, primary, Kawakibi, Abed Rahman, additional, Ji, Sunjong, additional, Waszak, Sebastian, additional, Sweha, Stefan, additional, Mota, Mateus, additional, Pun, Matthew, additional, Deogharkar, Akash, additional, Chung, Chan, additional, Tarapore, Rohinton, additional, Ramage, Samuel, additional, Wen, Patrick, additional, Arrillaga-Romany, Isabel, additional, Garton, Hugh, additional, Franson, Andrea, additional, Schwartz, Jonathan, additional, Jain, Rajan, additional, Mottl, Sophie, additional, Cartaxo, Rodrigo, additional, John, Vishal, additional, Messinger, Dana, additional, Qin, Tingting, additional, Peterson, Erik, additional, Sajjakulnukit, Peter, additional, Judkins, Alexander, additional, Wahl, Daniel, additional, Lyssiotis, Costas, additional, de la Nava, Daniel, additional, Alonso, Martha, additional, Duchatel, Ryan, additional, Dun, Matthew, additional, Cain, Jason, additional, Jiang, Li, additional, Filbin, Mariella, additional, Zhao, Lili, additional, Kumar-Sinha, Chandan, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Kurokawa, Ryo, additional, Pratt, Drew, additional, Yadav, Viveka, additional, Grill, Jacques, additional, Kline, Cassie, additional, Mueller, Sabine, additional, Resnick, Adam, additional, Nazarian, Javad, additional, Allen, Joshua, additional, Odia, Yazmin, additional, Gardner, Sharon, additional, and Koschmann, Carl, additional

Published
2023
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14. TMET-13. DNA DAMAGE SIGNALING ACTIVATES GTP SYNTHESIS TO PROMOTE GLIOBLASTOMA TREATMENT RESISTANCE

Author

Scott, Andrew J, primary, O'Brien, Alexandra, additional, Zhou, Weihua, additional, Xu, Jie, additional, Palavalasa, Sravya, additional, Kothari, Ayesha, additional, Wilder-Romans, Kari, additional, Lin, Angelica, additional, Zhao, Zitong, additional, Yang, Annabel, additional, Korimerla, Navyateja, additional, Peterson, Erik, additional, Yang, John, additional, Zhang, Li, additional, Andren, Anthony, additional, Chandrasekaran, Sriram, additional, Venneti, Sriram, additional, Heth, Jason, additional, Umemura, Yoshie, additional, Qi, Nathan, additional, Woulfe, John, additional, Morgan, Meredith, additional, Lawrence, Theodore, additional, Al-Holou, Wajd, additional, Lyssiotis, Costas, additional, and Wahl, Daniel, additional

Published
2023
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15. PDGFRA Amplification is Common in Pediatric and Adult High‐Grade Astrocytomas and Identifies a Poor Prognostic Group in IDH1 Mutant Glioblastoma

Author

Phillips, Joanna J, Aranda, Derick, Ellison, David W, Judkins, Alexander R, Croul, Sidney E, Brat, Daniel J, Ligon, Keith L, Horbinski, Craig, Venneti, Sriram, Zadeh, Gelareh, Santi, Mariarita, Zhou, Shengmei, Appin, Christina L, Sioletic, Stefano, Sullivan, Lisa M, Martinez‐Lage, Maria, Robinson, Aaron E, Yong, William H, Cloughesy, Timothy, Lai, Albert, Phillips, Heidi S, Marshall, Roxanne, Mueller, Sabine, Haas‐Kogan, Daphne A, Molinaro, Annette M, and Perry, Arie

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Brain Cancer, Neurosciences, Rare Diseases, Pediatric, Brain Disorders, Genetics, Adolescent, Adult, Astrocytoma, Brain Neoplasms, Child, Child, Preschool, Cohort Studies, DNA Copy Number Variations, Female, Glioblastoma, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Receptor, Platelet-Derived Growth Factor alpha, Sex Factors, Statistics, Nonparametric, Young Adult, astrocytoma, FISH, IDH1, isocitrate dehydrogenase 1, PDGFRA, prognosis, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

High-grade astrocytomas (HGAs), corresponding to World Health Organization grades III (anaplastic astrocytoma) and IV (glioblastoma; GBM), are biologically aggressive, and their molecular classification is increasingly relevant to clinical management. PDGFRA amplification is common in HGAs, although its prognostic significance remains unclear. Using fluorescence in situ hybridization (FISH), the most sensitive technique for detecting PDGFRA copy number gains, we determined PDGFRA amplification status in 123 pediatric and 263 adult HGAs. A range of PDGFRA FISH patterns were identified and cases were scored as non-amplified (normal and polysomy) or amplified (low-level and high-level). PDGFRA amplification was frequent in pediatric (29.3%) and adult (20.9%) tumors. Amplification was not prognostic in pediatric HGAs. In adult tumors diagnosed initially as GBM, the presence of combined PDGFRA amplification and isocitrate dehydrogenase 1 (IDH1)(R132H) mutation was a significant independent prognostic factor (P = 0.01). In HGAs, PDGFRA amplification is common and can manifest as high-level and focal or low-level amplifications. Our data indicate that the latter is more prevalent than previously reported with copy number averaging techniques. To our knowledge, this is the largest survey of PDGFRA status in adult and pediatric HGAs and suggests PDGFRA amplification increases with grade and is associated with a less favorable prognosis in IDH1 mutant de novo GBMs.

Published
2013

16. Histone 3 Lysine 9 Trimethylation Is Differentially Associated With Isocitrate Dehydrogenase Mutations in Oligodendrogliomas and High-Grade Astrocytomas

Author

Venneti, Sriram, Felicella, Michelle Madden, Coyne, Thomas, Phillips, Joanna J, Gorovets, Daniel, Huse, Jason T, Kofler, Julia, Lu, Chao, Tihan, Tarik, Sullivan, Lisa M, Santi, Mariarita, Judkins, Alexander R, Perry, Arie, and Thompson, Craig B

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Brain Cancer, Cancer, Genetics, Brain Disorders, Adolescent, Adult, Astrocytoma, Biomarkers, Tumor, Cell Survival, Child, DNA Methylation, DNA Mutational Analysis, Female, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Histones, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Oligodendroglioma, Glioma, H3K9me3, Histone methylation, Isocitrate dehydrogenase, Clinical Sciences, Neurosciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Trimethylation of histone 3 lysine 9 (H3K9me3) is a marker of repressed transcription. Cells transfected with mutant isocitrate dehydrogenase (IDH) show increased methylation of histone lysine residues, including H3K9me3, because of inhibition of histone demethylases by 2-hydroxyglutarate. Here, we evaluated H3K9me3 and its association with IDH mutations in 284 gliomas. Trimethylation of H3K9 was significantly associated with IDH mutations in oligodendrogliomas. Moreover, 72% of World Health Organization grade II and 65% of grade III oligodendrogliomas showed combined H3K9me3 positivity and 1p19q codeletion. In astrocytic tumors, H3K9me3 positivity was found in all grades of tumors; it showed a significant relationship with IDH mutational status in grade II astrocytomas but not in grade III astrocytomas or glioblastomas. Finally, H3K9me3-positive grade II oligodendrogliomas, but not other tumor subtypes, showed improved overall survival compared with H3K9me3-negative cases. These results suggest that repressive trimethylation of H3K9 in gliomas may occur in a context-dependent manner and is associated with IDH mutations in oligodendrogliomas but may be differently regulated in high-grade astrocytic tumors. Furthermore, H3K9me3 may define a subset of grade II oligodendrogliomas with better overall survival. Our results suggest variable roles for IDH mutations in the pathogenesis of oligodendrogliomas versus astrocytic tumors.

Published
2013

17. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary

Author

Xue, Yibo, Meehan, Brian, Macdonald, Elizabeth, Venneti, Sriram, Wang, Xue Qing D., Witkowski, Leora, Jelinic, Petar, Kong, Tim, Martinez, Daniel, Morin, Geneviève, Firlit, Michelle, Abedini, Atefeh, Johnson, Radia M., Cencic, Regina, Patibandla, Jay, Chen, Hongbo, Papadakis, Andreas I., Auguste, Aurelie, de Rink, Iris, Kerkhoven, Ron M., Bertos, Nicholas, Gotlieb, Walter H., Clarke, Blaise A., Leary, Alexandra, Witcher, Michael, Guiot, Marie-Christine, Pelletier, Jerry, Dostie, Josée, Park, Morag, Judkins, Alexander R., Hass, Ralf, Levine, Douglas A., Rak, Janusz, Vanderhyden, Barbara, Foulkes, William D., and Huang, Sidong

Published
2019
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18. SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer

Author

Xue, Yibo, Meehan, Brian, Fu, Zheng, Wang, Xue Qing D., Fiset, Pierre Olivier, Rieker, Ralf, Levins, Cameron, Kong, Tim, Zhu, Xianbing, Morin, Geneviève, Skerritt, Lashanda, Herpel, Esther, Venneti, Sriram, Martinez, Daniel, Judkins, Alexander R., Jung, Sungmi, Camilleri-Broet, Sophie, Gonzalez, Anne V., Guiot, Marie-Christine, Lockwood, William W., Spicer, Jonathan D., Agaimy, Abbas, Pastor, William A., Dostie, Josée, Rak, Janusz, Foulkes, William D., and Huang, Sidong

Published
2019
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19. β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

Author

Mohan, Dipika R., primary, Borges, Kleiton S., additional, Finco, Isabella, additional, LaPensee, Christopher R., additional, Rege, Juilee, additional, Solon, April L., additional, Little, Donald W., additional, Else, Tobias, additional, Almeida, Madson Q., additional, Dang, Derek, additional, Haggerty-Skeans, James, additional, Apfelbaum, April A., additional, Vinco, Michelle, additional, Wakamatsu, Alda, additional, Mariani, Beatriz M.P., additional, Amorim, Larissa Costa, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice B., additional, Zerbini, Maria Claudia N., additional, Lawlor, Elizabeth R., additional, Ohi, Ryoma, additional, Auchus, Richard J., additional, Rainey, William E., additional, Marie, Suely K.N., additional, Giordano, Thomas J., additional, Venneti, Sriram, additional, Fragoso, Maria Candida Barisson Villares, additional, Breault, David T., additional, Lerario, Antonio Marcondes, additional, and Hammer, Gary D., additional

Published
2023
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20. Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas

Author

Mota, Mateus, primary, Sweha, Stefan R., additional, Pun, Matt, additional, Natarajan, Siva Kumar, additional, Ding, Yujie, additional, Chung, Chan, additional, Hawes, Debra, additional, Yang, Fusheng, additional, Judkins, Alexander R., additional, Samajdar, Susanta, additional, Cao, Xuhong, additional, Xiao, Lanbo, additional, Parolia, Abhijit, additional, Chinnaiyan, Arul M., additional, and Venneti, Sriram, additional

Published
2023
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21. Abstract 6047: ZFTA-RELA fusion aberrantly drives glutamine metabolism in lethal pediatric ependymomas

Author

Natarajan, Siva Kumar, primary, Haggerty-Skeans, James, additional, Lum, Joanna, additional, Narayanan, Pranav, additional, Sweha, Stefan, additional, Sunil, Sushanth, additional, Panwalkar, Pooja, additional, Bayliss, Jill, additional, Sajjakulnukit, Peter, additional, Dang, Derek, additional, Achreja, Abhinav, additional, Nagrath, Deepak, additional, Lyssiotis, Costas, additional, and Venneti, Sriram, additional

Published
2023
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23. Abstract 1501: Epigenetic dedifferentiation as a therapeutic strategy in adrenal cancer

Author

Mohan, Dipika R., primary, Borges, Kleiton S., additional, Finco, Isabella, additional, LaPensee, Christopher R., additional, Rege, Juilee, additional, Little, Donald W., additional, Else, Tobias, additional, Almeida, Madson Q., additional, Dang, Derek, additional, Haggerty-Skeans, James, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice B., additional, Auchus, Richard J., additional, Rainey, William E., additional, Marie, Suely K., additional, Giordano, Thomas J., additional, Venneti, Sriram, additional, Fragoso, Maria Candida B., additional, Breault, David T., additional, Lerario, Antonio M., additional, and Hammer, Gary D., additional

Published
2023
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24. Abstract 3523: A systematic comparison of molecular features shared by H3K27-altered diffuse midline gliomas and posterior fossa A ependymomas

Author

Pun, Matthew, primary, Pratt, Drew, additional, Nano, Patricia R., additional, Joshi, Piyush K., additional, Jiang, Li, additional, Englinger, Bernhard, additional, Rao, Arvind, additional, Cieslik, Marcin, additional, Chinnaiyan, Arul M., additional, Aldape, Kenneth, additional, Pfister, Stefan, additional, Filbin, Mariella G., additional, Bhaduri, Aparna, additional, and Venneti, Sriram, additional

Published
2023
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25. Abstract 3677: DNA damage signaling activates de novo GTP synthesis to promote chemoradiation resistance in glioblastoma

Author

Scott, Andrew J., primary, O'Brien, Alexandra M., additional, Zhou, Weihua, additional, Pareek, Vidhi, additional, Sha, Zhou, additional, Palavalasa, Sravya, additional, Kothari, Ayesha U., additional, Wilder-Romans, Kari, additional, Zhang, Li, additional, Andren, Anthony C., additional, Chandrasekaran, Sriram, additional, Heth, Jason, additional, Umemura, Yoshie, additional, Qi, Nathan, additional, Woulfe, John, additional, Venneti, Sriram, additional, Morgan, Meredith A., additional, Lawrence, Theodore S., additional, Al-Holou, Wajd N., additional, Lyssiotis, Costas A., additional, and Wahl, Daniel R., additional

Published
2023
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26. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Author

Venneti, Sriram; https://orcid.org/0000-0001-9764-0423, Kawakibi, Abed Rahman; https://orcid.org/0000-0001-6347-8974, Ji, Sunjong; https://orcid.org/0000-0002-6516-2380, Waszak, Sebastian M; https://orcid.org/0000-0003-3042-9521, Sweha, Stefan R; https://orcid.org/0000-0002-1807-6770, Mota, Mateus; https://orcid.org/0009-0006-3126-8212, Pun, Matthew; https://orcid.org/0000-0002-4766-4301, Deogharkar, Akash; https://orcid.org/0009-0003-8980-0484, Chung, Chan; https://orcid.org/0000-0003-0510-8996, Tarapore, Rohinton S; https://orcid.org/0000-0002-8070-5646, Ramage, Samuel; https://orcid.org/0000-0002-0098-114X, Chi, Andrew; https://orcid.org/0000-0002-6642-1620, Wen, Patrick Y; https://orcid.org/0000-0002-0774-7700, Arrillaga-Romany, Isabel; https://orcid.org/0000-0001-5951-1225, Batchelor, Tracy T; https://orcid.org/0000-0001-7568-6607, Butowski, Nicholas A; https://orcid.org/0000-0001-5162-2406, Sumrall, Ashley; https://orcid.org/0000-0002-2863-203X, Shonka, Nicole; https://orcid.org/0000-0002-8182-3409, Harrison, Rebecca A; https://orcid.org/0000-0002-5689-8492, de Groot, John; https://orcid.org/0000-0003-1454-6461, Mehta, Minesh; https://orcid.org/0000-0002-4812-5713, Hall, Matthew D; https://orcid.org/0000-0001-8768-3577, Daghistani, Doured; https://orcid.org/0009-0007-2706-1611, Cloughesy, Timothy F; https://orcid.org/0000-0002-8656-7483, Ellingson, Benjamin M; https://orcid.org/0000-0002-2764-6640, Beccaria, Kevin; https://orcid.org/0000-0002-3405-1944, Varlet, Pascale; https://orcid.org/0000-0002-8164-1517, Kim, Michelle M; https://orcid.org/0000-0001-7566-6411, Mueller, Sabine; https://orcid.org/0000-0002-3452-5150, Nazarian, Javad; https://orcid.org/0000-0002-1951-9828, et al, Venneti, Sriram; https://orcid.org/0000-0001-9764-0423, Kawakibi, Abed Rahman; https://orcid.org/0000-0001-6347-8974, Ji, Sunjong; https://orcid.org/0000-0002-6516-2380, Waszak, Sebastian M; https://orcid.org/0000-0003-3042-9521, Sweha, Stefan R; https://orcid.org/0000-0002-1807-6770, Mota, Mateus; https://orcid.org/0009-0006-3126-8212, Pun, Matthew; https://orcid.org/0000-0002-4766-4301, Deogharkar, Akash; https://orcid.org/0009-0003-8980-0484, Chung, Chan; https://orcid.org/0000-0003-0510-8996, Tarapore, Rohinton S; https://orcid.org/0000-0002-8070-5646, Ramage, Samuel; https://orcid.org/0000-0002-0098-114X, Chi, Andrew; https://orcid.org/0000-0002-6642-1620, Wen, Patrick Y; https://orcid.org/0000-0002-0774-7700, Arrillaga-Romany, Isabel; https://orcid.org/0000-0001-5951-1225, Batchelor, Tracy T; https://orcid.org/0000-0001-7568-6607, Butowski, Nicholas A; https://orcid.org/0000-0001-5162-2406, Sumrall, Ashley; https://orcid.org/0000-0002-2863-203X, Shonka, Nicole; https://orcid.org/0000-0002-8182-3409, Harrison, Rebecca A; https://orcid.org/0000-0002-5689-8492, de Groot, John; https://orcid.org/0000-0003-1454-6461, Mehta, Minesh; https://orcid.org/0000-0002-4812-5713, Hall, Matthew D; https://orcid.org/0000-0001-8768-3577, Daghistani, Doured; https://orcid.org/0009-0007-2706-1611, Cloughesy, Timothy F; https://orcid.org/0000-0002-8656-7483, Ellingson, Benjamin M; https://orcid.org/0000-0002-2764-6640, Beccaria, Kevin; https://orcid.org/0000-0002-3405-1944, Varlet, Pascale; https://orcid.org/0000-0002-8164-1517, Kim, Michelle M; https://orcid.org/0000-0001-7566-6411, Mueller, Sabine; https://orcid.org/0000-0002-3452-5150, Nazarian, Javad; https://orcid.org/0000-0002-1951-9828, and et al

Abstract

UNLABELLED 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 multisite 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. SIGNIFICANCE The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Published
2023

27. H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models

Author

Haase, Santiago, primary, Banerjee, Kaushik, additional, Mujeeb, Anzar A., additional, Hartlage, Carson S., additional, Núñez, Fernando M., additional, Núñez, Felipe J., additional, Alghamri, Mahmoud S., additional, Kadiyala, Padma, additional, Carney, Stephen, additional, Barissi, Marcus N., additional, Taher, Ayman W., additional, Brumley, Emily K., additional, Thompson, Sarah, additional, Dreyer, Justin T., additional, Alindogan, Caitlin T., additional, Garcia-Fabiani, Maria B., additional, Comba, Andrea, additional, Venneti, Sriram, additional, Ravikumar, Visweswaran, additional, Koschmann, Carl, additional, Carcaboso, Ángel M., additional, Vinci, Maria, additional, Rao, Arvind, additional, Yu, Jennifer S., additional, Lowenstein, Pedro R., additional, and Castro, Maria G., additional

Published
2022
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28. RF21 | PSAT76 Epigenetic Programs Stabilize a Differentiated Cell State Required for Sustained Proliferation in Adrenocortical Carcinoma

Author

Mohan, Dipika, primary, Borges, Kleiton, additional, Finco, Isabella, additional, LaPensee, Christopher, additional, Rege, Juilee, additional, Little, Donald, additional, Else, Tobias, additional, Almeida, Madson, additional, Latronico, Ana Claudia, additional, Mendonca, Berenice, additional, Auchus, Richard, additional, Rainey, William, additional, Marie, Suely, additional, Giordano, Thomas, additional, Venneti, Sriram, additional, Candida Fragoso, Maria, additional, Breault, David, additional, Lerario, Antonio, additional, and Hammer, Gary, additional

Published
2022
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29. CSIG-09. THERAPEUTIC TARGETING OF PRENATAL PONTINE ID1 SIGNALING IN DIFFUSE MIDLINE GLIOMA

Author

Messinger, Dana, primary, Harris, Micah, additional, Cummings, Jessica, additional, Thomas, Chase, additional, Yang, Tao, additional, Sweha, Stefan, additional, Woo, Rinette, additional, Siddaway, Robert, additional, Burkert, Martin, additional, Stallard, Stefanie, additional, Qin, Tingting, additional, Mullan, Brendan, additional, Siada, Ruby, additional, Ravindran, Ramya, additional, Niculcea, Michael, additional, Dowling, Abigail, additional, Bradin, Joshua, additional, Ginn, Kevin, additional, Gener, Melissa, additional, Dorris, Kathleen, additional, Vitanza, Nicholas, additional, Schmidt, Susanne, additional, Spitzer, Jasper, additional, Li, Jiang, additional, Filbin, Mariella, additional, Cao, Xuhong, additional, Castro, Maria, additional, Lowenstein, Pedro, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Desprez, Pierre-Yves, additional, McAllister, Sean, additional, Dun, Matthew, additional, Hawkins, Cynthia, additional, Waszak, Sebastian, additional, Venneti, Sriram, additional, Koschmann, Carl, additional, and Yadav, Viveka, additional

Published
2022
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30. CTNI-61. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA

Author

Kawakibi, Abed Rahman, primary, Tarapore, Rohinton, additional, Gardner, Sharon, additional, Chi, Andrew, additional, Kurz, Sylvia, additional, Wen, Patrick Y, additional, Arrillaga-Romany, Isabel, additional, Batchelor, Tracy, additional, Butowski, Nicholas, additional, Sumrall, Ashley, additional, Shonka, Nicole, additional, Harrison, Rebecca, additional, DeGroot, John, additional, Mehta, Minesh, additional, Odia, Yazmin, additional, Hall, Matthew, additional, Daghistani, Doured, additional, Cloughesy, Timothy, additional, Ellingson, Benjamin, additional, Kim, Michelle, additional, Umemura, Yoshie, additional, Garton, Hugh, additional, Franson, Andrea, additional, Schwartz, Jonathan, additional, Li, Sunjong, additional, Cartaxo, Rodrigo, additional, Ravi, Karthik, additional, Cantor, Evan, additional, Cummings, Jessica, additional, Paul, Alyssa, additional, Walling, Dustin, additional, Dun, Matthew, additional, Cain, Jason, additional, Li, Jiang, additional, Filbin, Mariella, additional, Zhao, Lili, additional, Kumar-Sinha, Chandan, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Kurokawa, Ryo, additional, Pratt, Drew, additional, Venneti, Sriram, additional, Grill, Jacques, additional, Kline, Cassie, additional, Mueller, Sabine, additional, Resnick, Adam C, additional, Nazarian, Javad, additional, Waszak, Sebastian, additional, Allen, Joshua E, additional, and Koschmann, Carl, additional

Published
2022
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31. Akt-Dependent Metabolic Reprogramming Regulates Tumor Cell Histone Acetylation

Author

Lee, Joyce V., Carrer, Alessandro, Shah, Supriya, Snyder, Nathaniel W., Wei, Shuanzeng, Venneti, Sriram, Worth, Andrew J., Yuan, Zuo-Fei, Lim, Hee-Woong, Liu, Shichong, Jackson, Ellen, Aiello, Nicole M., Haas, Naomi B., Rebbeck, Timothy R., Judkins, Alexander, Won, Kyoung-Jae, Chodosh, Lewis A., Garcia, Benjamin A., Stanger, Ben Z., Feldman, Michael D., Blair, Ian A., and Wellen, Kathryn E.

Published
2014
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32. miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma

Author

Mathew, Lijoy K., Skuli, Nicolas, Mucaj, Vera, Lee, Samuel S., Zinn, Pascal O., Sathyan, Pratheesh, Imtiyaz, Hongxia Z., Zhang, Zhongfa, Davuluri, Ramana V., Rao, Shilpa, Venneti, Sriram, Lal, Priti, Lathia, Justin D., Rich, Jeremy N., Keith, Brian, Minn, Andy J., and Simon, M. Celeste

Published
2014

33. CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response

Author

Stallard, Stefanie, Savelieff, Masha G., Wierzbicki, Kyle, Mullan, Brendan, Miklja, Zachary, Bruzek, Amy, Garcia, Taylor, Siada, Ruby, Anderson, Bailey, Singer, Benjamin H., Hashizume, Rintaro, Carcaboso, Angel M., McMurray, Kaitlin Q., Heth, Jason, Muraszko, Karin, Robertson, Patricia L., Mody, Rajen, Venneti, Sriram, Garton, Hugh, and Koschmann, Carl

Published
2018
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34. Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry

Author

Gits, Hunter C., Anderson, Maia, Stallard, Stefanie, Pratt, Drew, Zon, Becky, Howell, Christopher, Kumar-Sinha, Chandan, Vats, Pankaj, Kasaian, Katayoon, Polan, Daniel, Matuszak, Martha, Spratt, Daniel E., Leonard, Marcia, Qin, Tingting, Zhao, Lili, Leach, James, Chaney, Brooklyn, Escorza, Nancy Yanez, Hendershot, Jacob, Jones, Blaise, Fuller, Christine, Leary, Sarah, Bartels, Ute, Bouffet, Eric, Yock, Torunn I., Robertson, Patricia, Mody, Rajen, Venneti, Sriram, Chinnaiyan, Arul M., Fouladi, Maryam, Gottardo, Nicholas G., and Koschmann, Carl

Published
2018
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37. Therapeutic targeting of prenatal pontine ID1 signaling in diffuse midline glioma

Author

Messinger, Dana, primary, Harris, Micah K, additional, Cummings, Jessica R, additional, Thomas, Chase, additional, Yang, Tao, additional, Sweha, Stefan R, additional, Woo, Rinette, additional, Siddaway, Robert, additional, Burkert, Martin, additional, Stallard, Stefanie, additional, Qin, Tingting, additional, Mullan, Brendan, additional, Siada, Ruby, additional, Ravindran, Ramya, additional, Niculcea, Michael, additional, Dowling, Abigail R, additional, Bradin, Joshua, additional, Ginn, Kevin F, additional, Gener, Melissa A H, additional, Dorris, Kathleen, additional, Vitanza, Nicholas A, additional, Schmidt, Susanne V, additional, Spitzer, Jasper, additional, Li, Jiang, additional, Filbin, Mariella G, additional, Cao, Xuhong, additional, Castro, Maria G, additional, Lowenstein, Pedro R, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Desprez, Pierre-Yves, additional, McAllister, Sean, additional, Dun, Matthew D, additional, Hawkins, Cynthia, additional, Waszak, Sebastian M, additional, Venneti, Sriram, additional, Koschmann, Carl, additional, and Yadav, Viveka Nand, additional

Published
2022
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39. Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma

Author

Cantor, Evan, primary, Wierzbicki, Kyle, additional, Tarapore, Rohinton S, additional, Ravi, Karthik, additional, Thomas, Chase, additional, Cartaxo, Rodrigo, additional, Nand Yadav, Viveka, additional, Ravindran, Ramya, additional, Bruzek, Amy K, additional, Wadden, Jack, additional, John, Vishal, additional, May Babila, Clarissa, additional, Cummings, Jessica R, additional, Rahman Kawakibi, Abed, additional, Ji, Sunjong, additional, Ramos, Johanna, additional, Paul, Alyssa, additional, Walling, Dustin, additional, Leonard, Marcia, additional, Robertson, Patricia, additional, Franson, Andrea, additional, Mody, Rajen, additional, Garton, Hugh J L, additional, Venneti, Sriram, additional, Odia, Yazmin, additional, Kline, Cassie, additional, Vitanza, Nicholas A, additional, Khatua, Soumen, additional, Mueller, Sabine, additional, Allen, Joshua E, additional, Gardner, Sharon L, additional, and Koschmann, Carl, additional

Published
2022
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40. ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization

Author

Qin, Tingting, primary, Mullan, Brendan, additional, Ravindran, Ramya, additional, Messinger, Dana, additional, Siada, Ruby, additional, Cummings, Jessica R., additional, Harris, Micah, additional, Muruganand, Ashwath, additional, Pyaram, Kalyani, additional, Miklja, Zachary, additional, Reiber, Mary, additional, Garcia, Taylor, additional, Tran, Dustin, additional, Danussi, Carla, additional, Brosnan-Cashman, Jacqueline, additional, Pratt, Drew, additional, Zhao, Xinyi, additional, Rehemtulla, Alnawaz, additional, Sartor, Maureen A., additional, Venneti, Sriram, additional, Meeker, Alan K., additional, Huse, Jason T., additional, Morgan, Meredith A., additional, Lowenstein, Pedro R., additional, Castro, Maria G., additional, Yadav, Viveka Nand, additional, and Koschmann, Carl, additional

Published
2022
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41. A road map for the treatment of pediatric diffuse midline glioma

Author

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, and Venneti, Sriram

Published
2024
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42. TAMI-79. THERAPEUTIC REVERSAL OF PRENATAL PONTINE ID1 SIGNALING IN DIPG

Author

Yadav, Viveka Nand, primary, Harris, Micah K, additional, Messinger, Dana, additional, Thomas, Chase, additional, Cummings, Jessica R, additional, Yang, Tao, additional, Woo, Rinette, additional, Siddaway, Robert, additional, Burkert, Martin, additional, Stallard, Stefanie, additional, Qin, Tingting, additional, Mullan, Brendan, additional, Siada, Ruby, additional, Ravindran, Ramya, additional, Niculcea, Michael, additional, Ginn, Kevin F, additional, Gener, Melissa A H, additional, Dorris, Kathleen, additional, Vitanza, Nicholas A, additional, Schmidt, Susanne V, additional, Spitzer, Jasper, additional, Li, Jiang, additional, Filbin, Mariella G, additional, Cao, Xuhong, additional, Castro, Maria G, additional, Lowenstein, Pedro R, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Desprez, Pierre, additional, McAllister, Sean, additional, Hawkins, Cynthia, additional, Waszak, Sebastian M, additional, Venneti, Sriram, additional, and Koschmann, Carl, additional

Published
2021
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46. EPCT-07. ID1 IS A KEY TRANSCRIPTIONAL REGULATOR OF DIPG INVASION AND IS TARGETABLE WITH CANNABIDIOL

Author

Nand Yadav, Viveka, primary, Harris, Micah K, additional, Thomas, Chase, additional, Stallard, Stefanie, additional, Woo, Rinette, additional, Siddaway, Robert, additional, Qin, Tingting, additional, Cummings, Jessica R, additional, Mullan, Brendan, additional, Siada, Ruby, additional, Ravindran, Ramya, additional, Niculcea, Michael, additional, Cao, Xuhong, additional, Castro, Maria G, additional, Lowenstein, Pedro R, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Hawkins, Cynthia, additional, Desprez, Pierre, additional, McAllister, Sean, additional, Venneti, Sriram, additional, and Koschmann, Carl, additional

Published
2021
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48. Everolimus improves the efficacy of dasatinib in the treatment of PDGFRA-driven glioma

Author

Miklja, Zachary, Yadav, Vivek Nand, Cartaxo, Rodrigo, Siada, Ruby, Mullan, Brendan, Stallard, Stefanie, Paul, Alyssa, Bruzek, Amy K., Wierzbicki, Kyle, Yang, Tao, Garcia, Taylor, Wolfe, Ian, Parmar, Hemant, Leonard, Marcia, Robertson, Patricia L., Garton, Hugh, Venneti, Sriram, Kumar-Sinha, Chandan, Chinnaiyan, Arul, Mody, Rajen, Manjunath, Pai P., Phoenix, Timothy N., Marini, Bernard L., and Koschmann, Carl

Subjects
hemic and lymphatic diseases, digestive system diseases
Abstract

Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. Treatment of PDGFRA-driven HGG with targeted agents, such as the tyrosine kinase inhibitor dasatinib, has failed in the clinic. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRA-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. Methods: Dose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. De novo tumors were generated in mice using intra-uterine electroporation (IUE) by injecting PB plasmids of TP53 mutation, PDGFRA mutation and H3K27M mutation (PPK) in the lateral vertical of mice embryos. Two children with recurrent PDGFRA-driven HGG were treated with dasatinib and everolimus with correlate CSF analysis. Results: Dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a dose-dependent reduction of PDGFRA and pPDGFRA. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Two children with recurrent PDGFRA-driven HGG treated with dasatinib and everolimus survived six months and nine months after progression. A paired CSF sample from the patient with PDGFRA-amplified HGG showed 50% increase in CSF dasatinib levels after the addition of everolimus. Conclusion: Efficacy of dasatinib treatment of PDGFRA-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population. Clinical Trial Registration ID # NCT03352427 .

Published
2020
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49. DIPG-59. UPREGULATION OF PRENATAL PONTINE ID1 SIGNALING IN DIPG

Author

Harris, Micah K, primary, Yadav, Viveka Nand, additional, Stallard, Stefanie, additional, Woo, Rinette, additional, Siddaway, Robert, additional, Qin, Tingting, additional, Mullan, Brendan, additional, Miklja, Zachary, additional, Siada, Ruby, additional, Ravindran, Ramya, additional, Cao, Xuhong, additional, Pasternak, Amy, additional, Castro, Maria G, additional, Lowenstein, Pedro R, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Hawkins, Cynthia, additional, Desprez, Pierre, additional, McAllister, Sean, additional, Venneti, Sriram, additional, and Koschmann, Carl, additional

Published
2020
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50. HGG-18. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA

Author

Kawakibi, Abed Rahman, primary, Tarapore, Rohinton S, additional, Gardner, Sharon, additional, Chi, Andrew, additional, Kurz, Sylvia, additional, Wen, Patrick Y, additional, Arrillaga-Romany, Isabel, additional, Batchelor, Tracy T, additional, Butowski, Nicholas A, additional, Sumrall, Ashley, additional, Shonka, Nicole, additional, Harrison, Rebecca, additional, DeGroot, John, additional, Mehta, Minesh, additional, Odia, Yazmin, additional, Hall, Matthew D, additional, Daghistani, Doured, additional, Cloughesy, Timothy F, additional, Ellingson, Benjamin M, additional, Umemura, Yoshie, additional, Schwartz, Jonathan, additional, Yadav, Vivekanand, additional, Cartaxo, Rodrigo, additional, Siada, Ruby, additional, Miklja, Zachary, additional, Bruzek, Amy, additional, Cantor, Evan, additional, Wierzbicki, Kyle, additional, Paul, Alyssa, additional, Wolfe, Ian, additional, Leaoard, Marcia, additional, Garton, Hugh, additional, Mody, Rajen, additional, Robertson, Patricia L, additional, Lu, Guangrong, additional, Merdinger, Krystal, additional, Venneti, Sriram, additional, Oster, Wolfgang, additional, Allen, Joshua E, additional, and Koschmann, Carl, additional

Published
2020
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