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1,413 results on '"Harrison, Rebecca A."'

1. Rosai-Dorfman-Destombes disease in adults: a single center experience

Author

Leung, Emily, Pryma, Collin, Murphy, Stephen, Harrison, Rebecca, Peterson, Erica, Tsang, Peter W. K., Varghese, Julia, You, Xiaotian (Julie), Slack, Graham W., Skinnider, Brian F., Ng, Tony, Young, Sean, Burrell, Steven, Stubbins, Ryan, Lim, Howard, Carruthers, Mollie, Dutz, Jan, Diamond, Eli L., and Chen, Luke Y. C.

Published
2024
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3. 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

15. Cycle Threshold Values as Indication of Increasing SARS-CoV-2 New Variants, England, 2020-2022

Author

Harrison, Rebecca E., Hamada, Ahmed, Haswell, Nujcharee, Groves, Aigul, Vihta, Karina-Doris, Cella, Kerry, Garner, Sarah, Walker, Ann Sarah, and Seale, Anna C.

Subjects
Infection -- Health aspects -- Analysis, Health
Abstract

From identification of SARS-CoV-2 in December 2019 through September 22, 2022, [approximately equal to] 612 million confirmed cases and 6.5 million confirmed deaths were reported worldwide (1). During the COVID-19 [...]

Published
2023
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17. Merleau-Ponty and Standpoint Theory

Author

Harrison, Rebecca, de Warren, Nicolas, Series Editor, Toadvine, Ted, Series Editor, Alweiss, Lilian, Editorial Board Member, Behnke, Elizabeth, Editorial Board Member, Bernet, Rudolf, Editorial Board Member, Carr, David, Editorial Board Member, Cheung, Chan-Fai, Editorial Board Member, Dodd, James, Editorial Board Member, Ferrarin, Alfredo, Editorial Board Member, Hopkins, Burt, Editorial Board Member, Huertas-Jourda, José, Editorial Board Member, Lau, Kwok-Ying, Editorial Board Member, Lee, Nam-In, Editorial Board Member, Lohmar, Dieter, Editorial Board Member, McKenna, William R., Editorial Board Member, Mickunas, Algis, Editorial Board Member, Mohanty, J. N., Editorial Board Member, Moran, Dermot, Editorial Board Member, Murata, Junichi, Editorial Board Member, Nenon, Thomas, Editorial Board Member, Soffer, Gail, Editorial Board Member, Steinbock, Anthony, Editorial Board Member, Taguchi, Shigeru, Editorial Board Member, Zahavi, Dan, Editorial Board Member, Zaner, Richard M., Editorial Board Member, Yoshimi, Jeff, editor, Walsh, Philip, editor, and Londen, Patrick, editor

Published
2023
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18. Preface

Author

Harrison, Rebecca L.

Published
2023

21. A genetic and pharmacogenetic study of clozapine in schizophrenia

Author

Harrison, Rebecca Naomi Storm, Breen, Gerome Daniel, Dobson, Richard James Butler, and De Jong, Simone

Subjects
615.7
Abstract

Treatment-resistant schizophrenia is diagnosed after unsuccessful trials of two or more antipsychotics. Clozapine has demonstrated efficacy in treatment-resistant patients but requires extensive monitoring to attain therapeutic plasma concentrations and prevent adverse effects. As a result, there is great clinical demand for characterization of intra-individual and population level variation in the progression of weight gain and for the attainment of therapeutically active clozapine plasma concentrations. Identifying such factors could stratify patients into homogeneous groups to receive targeted treatment interventions to improve patient adherence and prevent the risk of relapse or toxicity related adverse events. This thesis utilizes two cohorts; a clinical trial population of individuals with psychosis on a variety of medications and a large UK-based cohort of clozapine treated patients derived from therapeutic monitoring records. These cohorts are used to explore the contributory factors to psychotropic medication induced weight gain, with a focus on gene expression, genetics, and clinical factors. Using a variety of modelling approaches, this thesis identified associations between demographic factors and antipsychotic induced weight gain, and proposes a profile of individuals most at risk of antipsychotic weight gain. The factors influencing clozapine plasma concentrations are also outlined.

Published
2019

22. The Infant KIdney Dialysis and Utrafiltration (I-KID) Study: A Stepped-Wedge Cluster-Randomized Study in Infants, Comparing Peritoneal Dialysis, Continuous Venovenous Hemofiltration, and Newcastle Infant Dialysis Ultrafiltration System, a Novel Infant Hemodialysis Device

Author

Lambert, Heather, Hiu, Shaun, Coulthard, Malcolm G., Matthews, John N. S., Holstein, Eva-Maria, Crosier, Jean, Agbeko, Rachel, Brick, Thomas, Duncan, Heather, Grant, David, Mok, Quen, Nyman, Andrew Gustaf, Pappachan, John, Boucher, Chris, Bulmer, Joe, Chisholm, Denise, Cromie, Kirsten, Emmet, Victoria, Feltbower, Richard G., Ghose, Arunoday, Grayling, Michael, Harrison, Rebecca, Kennedy, Ciara A., McColl, Elaine, Morris, Kevin, Norman, Lee, Office, Julie, Parslow, Roger, Pattinson, Christine, Sharma, Shriya, Smith, Jonathan, Steel, Alison, Steel, Rachel, Straker, Jayne, Vrana, Lamprini, Walker, Jenn, Wellman, Paul, Whitaker, Mike, Wightman, Jim, Wilson, Nina, Wirz, Lucy, and Wood, Ruth

Published
2023
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24. Patient and health-care provider experience of a person-centred, multidisciplinary, psychosocial support and harm reduction programme for patients with harmful use of alcohol and drug-resistant tuberculosis in Minsk, Belarus

Author

Harrison, Rebecca Elizabeth, Shyleika, Volha, Falkenstein, Christian, Garsevanidze, Ekaterine, Vishnevskaya, Olga, Lonnroth, Knut, Sayakci, Öznur, Sinha, Animesh, Sitali, Norman, Skrahina, Alena, Stringer, Beverley, Tan, Cecilio, Mar, Htay Thet, Venis, Sarah, Vetushko, Dmitri, Viney, Kerri, Vishneuski, Raman, and Carrion Martin, Antonio Isidro

Published
2022
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25. Neurologic Toxicities of Immunotherapy

Author

Harrison, Rebecca A., Majd, Nazanin K., Tummala, Sudhakar, de Groot, John F., Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Steinlein, Ortrud, Series Editor, Xiao, Junjie, Series Editor, Naing, Aung, editor, and Hajjar, Joud, editor

Published
2021
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27. The need for more inclusive deliberation on ethics and governance in agricultural and food biotechnology

Author

Kendig, Catherine, primary, Selfa, Theresa, additional, Thompson, Paul B., additional, Anthony, Raymond, additional, Bauchspies, Wenda, additional, Blue, Gwendolyn, additional, Das, Ashmita, additional, Harrison, Rebecca, additional, Henke, Chris, additional, Jin, Shan, additional, Kuzma, Jennifer, additional, Lipschitz, Forbes, additional, Richter, Kurt, additional, Ruelle, Morgan, additional, Silberg, Timothy, additional, and Takahashi, Bruno, additional

Published
2024
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29. ONC201 (Dordaviprone) in Recurrent H3 K27M–Mutant Diffuse Midline Glioma

Author

Arrillaga-Romany, Isabel, primary, Gardner, Sharon L., additional, Odia, Yazmin, additional, Aguilera, Dolly, additional, Allen, Joshua E., additional, Batchelor, Tracy, additional, Butowski, Nicholas, additional, Chen, Clark, additional, Cloughesy, Timothy, additional, Cluster, Andrew, additional, de Groot, John, additional, Dixit, Karan S., additional, Graber, Jerome J., additional, Haggiagi, Aya M., additional, Harrison, Rebecca A., additional, Kheradpour, Albert, additional, Kilburn, Lindsay B., additional, Kurz, Sylvia C., additional, Lu, Guangrong, additional, MacDonald, Tobey J., additional, Mehta, Minesh, additional, Melemed, Allen S., additional, Nghiemphu, Phioanh Leia, additional, Ramage, Samuel C., additional, Shonka, Nicole, additional, Sumrall, Ashley, additional, Tarapore, Rohinton S., additional, Taylor, Lynne, additional, Umemura, Yoshie, additional, and Wen, Patrick Y., additional

Published
2024
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33. Significant Locus and Metabolic Genetic Correlations Revealed in Genome-Wide Association Study of Anorexia Nervosa

Author

Duncan, Laramie, Yilmaz, Zeynep, Gaspar, Helena, Walters, Raymond, Goldstein, Jackie, Anttila, Verneri, Bulik-Sullivan, Brendan, Ripke, Stephan, Thornton, Laura, Hinney, Anke, Daly, Mark, Sullivan, Patrick F, Zeggini, Eleftheria, Breen, Gerome, Bulik, Cynthia M, Gaspar, Héléna, Adan, Roger, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole, Aschauer, Harald, Baker, Jessica, Barrett, Jeffrey, Bencko, Vladimir, Bergen, Andrew, Berrettini, Wade, Birgegård, Andreas, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Cesta, Carolyn, Cichon, Sven, Clementi, Maurizio, Cohen-Woods, Sarah, Coleman, Joni, Cone, Roger, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, Jim, Danner, Unna, Davis, Oliver, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece, Dick, Danielle, Dikeos, Dimitris, Dina, Christian, Ding, Bo, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Espeseth, Thomas, Estivill, Xavier, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred, Finan, Chris, Fischer, Krista, Floyd, James, Föcker, Manuel, Foretova, Lenka, Forzan, Monica, Fox, Caroline, Franklin, Christopher, Gaborieau, Valerie, Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine, Harrison, Rebecca, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske, Hendriks, Judith, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, and Hilliard, Christopher

Subjects
Serious Mental Illness, Mental Health, Anorexia, Eating Disorders, Brain Disorders, Nutrition, Human Genome, Genetics, Prevention, Pediatric, Mental health, Anorexia Nervosa, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Eating Disorders Working Group of the Psychiatric Genomics Consortium, Diabetes, GWAS, Metabolism, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

ObjectiveThe authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes.MethodFollowing uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes.ResultsResults were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes.ConclusionsAnorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Published
2017

40. Table S4 from 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, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary

Published
2023
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41. INNV-35. IMPLEMENTATION OF A NATIONAL ADOLESCENT AND YOUNG ADULT MOLECULAR TUMOR BOARD: REPORT FROM THE CANADIAN AYA NEURO-ONCOLOGY NETWORK

Author

Lim-Fat, Mary-Jane, primary, Das, Sunit, additional, Climans, Seth, additional, MacDonald, Maria, additional, Perreault, Sébastien, additional, Yip, Stephen, additional, Harrison, Rebecca, additional, Lapointe, Sarah, additional, Chan, Aimee, additional, Massey, Natalie, additional, Erker, Craig, additional, MacNeil, Mary, additional, Ironside, Sarah, additional, Tsang, Derek, additional, Hawkins, Cynthia, additional, Tabori, Uri, additional, and Bennett, Julie, additional

Published
2023
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42. Supplementary Figures 1-15 from 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, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary

Published
2023
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43. Supplementary Data S2 from 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, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary

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

Published
2023
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49. 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

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