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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. 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

3. Near real-time intraoperative brain tumor diagnosis using stimulated Raman histology and deep neural networks.

Author

Hollon, Todd C, Pandian, Balaji, Adapa, Arjun R, Urias, Esteban, Save, Akshay V, Khalsa, Siri Sahib S, Eichberg, Daniel G, D'Amico, Randy S, Farooq, Zia U, Lewis, Spencer, Petridis, Petros D, Marie, Tamara, Shah, Ashish H, Garton, Hugh JL, Maher, Cormac O, Heth, Jason A, McKean, Erin L, Sullivan, Stephen E, Hervey-Jumper, Shawn L, Patil, Parag G, Thompson, B Gregory, Sagher, Oren, McKhann, Guy M, Komotar, Ricardo J, Ivan, Michael E, Snuderl, Matija, Otten, Marc L, Johnson, Timothy D, Sisti, Michael B, Bruce, Jeffrey N, Muraszko, Karin M, Trautman, Jay, Freudiger, Christian W, Canoll, Peter, Lee, Honglak, Camelo-Piragua, Sandra, and Orringer, Daniel A

Subjects
Humans, Brain Neoplasms, Monitoring, Intraoperative, Spectrum Analysis, Raman, Probability, Algorithms, Computer Systems, Image Processing, Computer-Assisted, Clinical Trials as Topic, Deep Learning, Neural Networks, Computer, Monitoring, Intraoperative, Spectrum Analysis, Raman, Image Processing, Computer-Assisted, Neural Networks, Computer, Medical and Health Sciences, Immunology
Abstract

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce4. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)5-7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)2. In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.

Published
2020

9. 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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10. 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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11. BIOM-58. ZERO-WASTE MOLECULAR DIAGNOSTICS FROM BIOPSY NEEDLE WASHES

Author

Wadden, Jack, primary, John, Vishal, additional, Niculcea, Michael, additional, Kong, Seongbae, additional, Aittaleb, Rayan, additional, Cartaxo, Rodrigo, additional, Verbal, Kait, additional, Bruzek, Amy, additional, Magge, Suresh, additional, Yadavilli, Sridevi, additional, Erez, Nir, additional, Furth, Noa, additional, Shema, Efrat, additional, Marapudi, Neena, additional, Heth, Jason, additional, Al-holou, Wajd, additional, Garton, Hugh, additional, Nazarian, Javad, additional, and Koschmann, Carl, additional

Published
2023
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12. 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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13. 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. 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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15. 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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17. 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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24. Data from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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25. Supplementary Table S3A and S3B from Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma

Author

Bruzek, Amy K., primary, Ravi, Karthik, primary, Muruganand, Ashwath, primary, Wadden, Jack, primary, Babila, Clarissa May, primary, Cantor, Evan, primary, Tunkle, Leo, primary, Wierzbicki, Kyle, primary, Stallard, Stefanie, primary, Dickson, Robert P., primary, Wolfe, Ian, primary, Mody, Rajen, primary, Schwartz, Jonathan, primary, Franson, Andrea, primary, Robertson, Patricia L., primary, Muraszko, Karin M., primary, Maher, Cormac O., primary, Garton, Hugh J.L., primary, Qin, Tingtin, primary, and Koschmann, Carl, primary

Published
2023
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26. Table S2 from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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27. Supplementary Figure 1 from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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28. Supplementary Figure 2 from Rapid Intraoperative Diagnosis of Pediatric Brain Tumors Using Stimulated Raman Histology

Author

Hollon, Todd C., primary, Lewis, Spencer, primary, Pandian, Balaji, primary, Niknafs, Yashar S., primary, Garrard, Mia R., primary, Garton, Hugh, primary, Maher, Cormac O., primary, McFadden, Kathryn, primary, Snuderl, Matija, primary, Lieberman, Andrew P., primary, Muraszko, Karin, primary, Camelo-Piragua, Sandra, primary, and Orringer, Daniel A., primary

Published
2023
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29. Supplementary Data from Electronic DNA Analysis of CSF Cell-free Tumor DNA to Quantify Multi-gene Molecular Response in Pediatric High-grade Glioma

Author

Bruzek, Amy K., primary, Ravi, Karthik, primary, Muruganand, Ashwath, primary, Wadden, Jack, primary, Babila, Clarissa May, primary, Cantor, Evan, primary, Tunkle, Leo, primary, Wierzbicki, Kyle, primary, Stallard, Stefanie, primary, Dickson, Robert P., primary, Wolfe, Ian, primary, Mody, Rajen, primary, Schwartz, Jonathan, primary, Franson, Andrea, primary, Robertson, Patricia L., primary, Muraszko, Karin M., primary, Maher, Cormac O., primary, Garton, Hugh J.L., primary, Qin, Tingtin, primary, and Koschmann, Carl, primary

Published
2023
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31. Characteristics of activation of monocyte-derived macrophages versus microglia after mouse experimental intracerebral hemorrhage.

Author

Ye, Fenghui, Yang, Jinting, Holste, Katherine G, Koduri, Sravanthi, Hua, Ya, Keep, Richard F, Garton, Hugh JL, and Xi, Guohua

Abstract

Both monocyte-derived macrophages (MDMs) and brain resident microglia participate in hematoma resolution after intracerebral hemorrhage (ICH). Here, we utilized a transgenic mouse line with enhanced green fluorescent protein (EGFP) labeled microglia (Tmem119-EGFP mice) combined with a F4/80 immunohistochemistry (a pan-macrophage marker) to visualize changes in MDMs and microglia after ICH. A murine model of ICH was used in which autologous blood was stereotactically injected into the right basal ganglia. The autologous blood was co-injected with CD47 blocking antibodies to enhance phagocytosis or clodronate liposomes for phagocyte depletion. In addition, Tmem119-EGFP mice were injected with the blood components peroxiredoxin 2 (Prx2) or thrombin. MDMs entered the brain and formed a peri-hematoma cell layer by day 3 after ICH and giant phagocytes engulfed red blood cells were found. CD47 blocking antibody increased the number of MDMs around and inside the hematoma and extended MDM phagocytic activity to day 7. Both MDMs and microglia could be diminished by clodronate liposomes. Intracerebral injection of Prx2 but not thrombin attracted MDMs into brain parenchyma. In conclusion, MDMs play an important role in phagocytosis after ICH which can be enhanced by CD47 blocking antibody, suggesting the modulation of MDMs after ICH could be a future therapeutic target. [ABSTRACT FROM AUTHOR]

Published
2023
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32. 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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35. Blood-brain barrier–adapted precision medicine therapy for pediatric brain tumors

Author

Marini, Bernard L., Benitez, Lydia L., Zureick, Andrew H., Salloum, Ralph, Gauthier, Angela C., Brown, Julia, Wu, Yi-Mi, Robinson, Dan R., Kumar, Chandan, Lonigro, Robert, Vats, Pankaj, Cao, Xuhong, Kasaian, Katayoon, Anderson, Bailey, Mullan, Brendan, Chandler, Benjamin, Linzey, Joseph R., Camelo-Piragua, Sandra I., Venneti, Sriram, McKeever, Paul E., McFadden, Kathryn A., Lieberman, Andrew P., Brown, Noah, Shao, Lina, Leonard, Marcia A.S., Junck, Larry, McKean, Erin, Maher, Cormac O., Garton, Hugh J.L., Muraszko, Karin M., Hervey-Jumper, Shawn, Mulcahy-Levy, Jean M., Green, Adam, Hoffman, Lindsey M., Dorris, Katie, Vitanza, Nicholas A., Wang, Joanne, Schwartz, Jonathan, Lulla, Rishi, Smiley, Natasha Pillay, Bornhorst, Miriam, Haas-Kogan, Daphne A., Robertson, Patricia L., Chinnaiyan, Arul M., Mody, Rajen, and Koschmann, Carl

Published
2017
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36. 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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44. 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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48. BIOM-28. SERIAL PLASMA AND CSF CELL-FREE TUMOR DNA (cf-tDNA) TRACKING IN DIFFUSE MIDLINE GLIOMA PATIENTS UNDERGOING TREATMENT WITH ONC201

Author

Cantor, Evan, primary, Wierzbicki, Kyle, additional, Tarapore, Rohinton, additional, Ravi, Karthik, additional, Wadden, Jack, additional, Babilla, Clarissa, additional, Thomas, Chase, additional, Cartaxo, Rodrigo, additional, Yadav, Vivek Anand, additional, Ravindran, Ramya, additional, Bruzek, Amy K, additional, Cummings, Jessica, additional, Kawakibi, Abed Rahman, additional, Ji, Sunjong, additional, Paul, Alyssa, additional, Wolfe, Ian, additional, Leonard, Marcia, additional, Robertson, Patricia, additional, Franson, Andrea, additional, Mody, Rajen, additional, Garton, Hugh, additional, Odia, Yazmin, additional, Kline, Cassie, additional, Vitanza, Nicholas, additional, Khatua, Soumen, additional, Allen, Joshua, additional, Mueller, Sabine, additional, Gardner, Sharon, additional, and Koschmann, Carl, additional

Published
2021
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50. 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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