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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. Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance.

Author

Carney, Stephen, Banerjee, Kaushik, Mujeeb, Anzar, Zhu, Brandon, Haase, Santiago, Varela, Maria, Kadiyala, Padma, Tronrud, Claire, Zhu, Ziwen, Mukherji, Devarshi, Gorla, Preethi, Sun, Yilun, Tagett, Rebecca, Núñez, Felipe, Luo, Maowu, Luo, Weibo, Ljungman, Mats, Liu, Yayuan, Xia, Ziyun, Schwendeman, Anna, Qin, Tingting, Sartor, Maureen, Cahill, Daniel, Lowenstein, Pedro, Castro, Maria, and Costello, Joseph

Subjects
Humans, Isocitrate Dehydrogenase, MYND Domains, Epigenesis, Genetic, Nuclear Proteins, Poly(ADP-ribose) Polymerase Inhibitors, Transcription Factors, Glioma, Cell Cycle Proteins
Abstract

PURPOSE: Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1 to confer therapeutic resistance to ionizing radiation (IR). EXPERIMENTAL DESIGN: We evaluated changes in the transcriptome and epigenome in a radioresistant mIDH1 patient-derived glioma cell culture (GCC) following treatment with an mIDH1-specific inhibitor, AGI-5198. We identified Zinc Finger MYND-Type Containing 8 (ZMYND8) as a potential target of mIDH1 reprogramming. We suppressed ZMYND8 expression by shRNA knockdown and genetic knockout (KO) in mIDH1 glioma cells and then assessed cellular viability to IR. We assessed the sensitivity of mIDH1 GCCS to pharmacologic inhibition of ZMYND8-interacting partners: HDAC, BRD4, and PARP. RESULTS: Inhibition of mIDH1 leads to an upregulation of gene networks involved in replication stress. We found that the expression of ZMYND8, a regulator of DNA damage response, was decreased in three patient-derived mIDH1 GCCs after treatment with AGI-5198. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 KO exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. CONCLUSIONS: These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma. See related commentary by Sachdev et al., p. 1648.

Published
2023

10. Supplementary Figures S1-S17 from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

Published
2024
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11. Supplementary Table S2 from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

Published
2024
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12. Data from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

Published
2024
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13. Supplementary Methods S1 from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

Published
2024
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15. 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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16. 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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17. 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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18. 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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19. 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 M., additional, Sweha, Stefan R., additional, Mota, Mateus, additional, Pun, Matthew, additional, Deogharkar, Akash, additional, Chung, Chan, additional, Tarapore, Rohinton S., additional, Ramage, Samuel, additional, Chi, Andrew, 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 A., additional, de Groot, John, additional, Mehta, Minesh, additional, Hall, Matthew D., additional, Daghistani, Doured, additional, Cloughesy, Timothy F., additional, Ellingson, Benjamin M., additional, Beccaria, Kevin, additional, Varlet, Pascale, additional, Kim, Michelle M., additional, Umemura, Yoshie, additional, Garton, Hugh, additional, Franson, Andrea, additional, Schwartz, Jonathan, additional, Jain, Rajan, additional, Kachman, Maureen, additional, Baum, Heidi, additional, Burant, Charles F., additional, Mottl, Sophie L., additional, Cartaxo, Rodrigo T., additional, John, Vishal, additional, Messinger, Dana, additional, Qin, Tingting, additional, Peterson, Erik, additional, Sajjakulnukit, Peter, additional, Ravi, Karthik, additional, Waugh, Alyssa, additional, Walling, Dustin, additional, Ding, Yujie, additional, Xia, Ziyun, additional, Schwendeman, Anna, additional, Hawes, Debra, additional, Yang, Fusheng, additional, Judkins, Alexander R., additional, Wahl, Daniel, additional, Lyssiotis, Costas A., additional, de la Nava, Daniel, additional, Alonso, Marta M., additional, Eze, Augustine, additional, Spitzer, Jasper, additional, Schmidt, Susanne V., additional, Duchatel, Ryan J., additional, Dun, Matthew D., additional, Cain, Jason E., additional, Jiang, Li, additional, Stopka, Sylwia A., additional, Baquer, Gerard, additional, Regan, Michael S., additional, Filbin, Mariella G., additional, Agar, Nathalie Y.R., additional, Zhao, Lili, additional, Kumar-Sinha, Chandan, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Kurokawa, Ryo, additional, Pratt, Drew, additional, Yadav, Viveka N., additional, Grill, Jacques, additional, Kline, Cassie, additional, Mueller, Sabine, additional, Resnick, Adam, additional, Nazarian, Javad, additional, Allen, Joshua E., additional, Odia, Yazmin, additional, Gardner, Sharon L., additional, and Koschmann, Carl, additional

Published
2023
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20. Supplementary Table S1 from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

Published
2023
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21. Data from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

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2023
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22. Supplementary Methods S1 from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

Published
2023
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23. Supplementary Figures S1-S17 from Zinc Finger MYND-Type Containing 8 (ZMYND8) Is Epigenetically Regulated in Mutant Isocitrate Dehydrogenase 1 (IDH1) Glioma to Promote Radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, primary, Mujeeb, Anzar, primary, Zhu, Brandon, primary, Haase, Santiago, primary, Varela, Maria L., primary, Kadiyala, Padma, primary, Tronrud, Claire E., primary, Zhu, Ziwen, primary, Mukherji, Devarshi, primary, Gorla, Preethi, primary, Sun, Yilun, primary, Tagett, Rebecca, primary, Núñez, Felipe J., primary, Luo, Maowu, primary, Luo, Weibo, primary, Ljungman, Mats, primary, Liu, Yayuan, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Qin, Tingting, primary, Sartor, Maureen A., primary, Costello, Joseph F., primary, Cahill, Daniel P., primary, Lowenstein, Pedro R., primary, and Castro, Maria G., primary

Published
2023
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24. Phospholipids impact the protective effects of HDL-mimetic nanodiscs against lipopolysaccharide-induced inflammation.

Author

Kim, Sang Yeop, Kang, Jukyung, Fawaz, Maria V, Yu, Minzhi, Xia, Ziyun, Morin, Emily E, Mei, Ling, Olsen, Karl, Li, Xiang-An, and Schwendeman, Anna

Abstract

Aim: The impacts of synthetic high-density lipoprotein (sHDL) phospholipid components on anti-sepsis effects were investigated. Methods: sHDL composed with ApoA-I mimetic peptide (22A) and different phosphatidylcholines were prepared and characterized. Anti-inflammatory effects were investigated in vitro and in vivo on lipopolysaccharide (LPS)-induced inflammation models. Results: sHDLs composed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (22A-DMPC) most effectively neutralizes LPS, inhibits toll-like receptor 4 recruitment into lipid rafts, suppresses nuclear factor κB signaling and promotes activating transcription factor 3 activating. The lethal endotoxemia animal model showed the protective effects of 22A-DMPC. Conclusion: Phospholipid components affect the stability and fluidity of nanodiscs, impacting the anti-septic efficacy of sHDLs. 22A-DMPC presents the strongest LPS binding and anti-inflammatory effects in vitro and in vivo, suggesting a potential sepsis treatment. Sepsis is triggered by endotoxins released by bacteria. These endotoxins trigger an exaggerated inflammatory response, leading to widespread inflammation and organ damage. Synthetic high-density lipoprotein (sHDL) is a potential treatment of sepsis by neutralizing endotoxins and regulating inflammatory responses. The phospholipid components of sHDL may affect the effectiveness of sHDL against sepsis. In this study, we prepared sHDLs with different phospholipids and compared their anti-septic effects on cells and in animal models. We found that sHDL made from DMPC presented the best anti-septic effects, possibly because DMPC-sHDL had the best fluidity at body temperature. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

Author

Carney, Stephen V., primary, Banerjee, Kaushik, additional, Mujeeb, Anzar, additional, Zhu, Brandon, additional, Haase, Santiago, additional, Varela, Maria L., additional, Kadiyala, Padma, additional, Tronrud, Claire, additional, Zhu, Ziwen, additional, Mukherji, Devarshi, additional, Gorla, Preethi, additional, Tagett, Rebecca, additional, Núñez, Felipe J., additional, Luo, Maowu, additional, Lou, Weibo, additional, Ljungman, Mats, additional, Liu, Yayuan, additional, Xia, Ziyun, additional, Schwendeman, Anna, additional, Qin, Tingting, additional, Sartor, Maureen A., additional, Costello, Joseph, additional, Cahill, Daniel P., additional, Lowenstein, Pedro R., additional, and Castro, Maria G., additional

Published
2022
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29. Phospholipid Component Defines Pharmacokinetic and Pharmacodynamic Properties of Synthetic High-Density Lipoproteins.

Author

Fawaz MV, Kim SY, Li D, Ming R, Xia Z, Olsen K, Pogozheva ID, Tesmer JJG, and Schwendeman A

Subjects
Amino Acid Sequence, Animals, Atherosclerosis prevention & control, Cholesterol chemistry, Cholesterol metabolism, Drug Delivery Systems, Drug Stability, Humans, Lipoproteins, HDL administration & dosage, Lipoproteins, HDL chemistry, Male, Molecular Structure, Nanoparticles administration & dosage, Peptides administration & dosage, Plaque, Atherosclerotic metabolism, Rats, Sprague-Dawley, Structure-Activity Relationship, Apolipoprotein A-I chemistry, Lipoproteins, HDL pharmacokinetics, Nanoparticles chemistry, Peptides chemistry, Peptides pharmacokinetics, Phospholipids chemistry
Abstract

Synthetic high-density lipoprotein (sHDL) nanoparticles composed of apolipoprotein A-I mimetic peptide and phospholipids have been shown to reduce atherosclerosis in animal models. Cholesterol is mobilized from atheroma macrophages by sHDL into the blood compartment and delivered to the liver for elimination. Historically, sHDL drug discovery efforts were focused on optimizing peptide sequences for interaction with cholesterol cellular transporters rather than understanding how both sHDL components, peptide and lipid, influence its pharmacokinetic and pharmacodynamic profiles. We designed two sets of sHDL having either identical phospholipid but variable peptide sequences with different plasma stability or identical peptide and phospholipids with variable fatty acid chain length and saturation. We found that sHDL prepared with proteolytically stable 22A-P peptide had 2-fold longer circulation half-time relative to the less stable 22A peptide. Yet, longer half-life did not translate into any improvement in cholesterol mobilization. In contrast, sHDL with variable phospholipid compositions showed significant differences in phospholipid PK, with distearoyl phosphatidylcholine-based sHDL demonstrating the longest half-life of 6.0 hours relative to 1.0 hour for palmitoyl-oleoyl phosphatidylcholine-based sHDL. This increase in half-life corresponded to an approx. 6.5-fold increase in the area under the curve for the mobilized cholesterol. Therefore, the phospholipid component in sHDL plays a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL. SIGNIFICANCE STATEMENT: The phospholipid composition in sHDL plays a critical role in determining half-life and cholesterol mobilization in vivo., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Published
2020
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