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3. Impact of trametinib on the neuropsychological profile of NF1 patients

Author

Lalancette, Eve, Cantin, Édith, Routhier, Marie-Ève, Mailloux, Chantal, Bertrand, Marie-Claude, Kiaei, Dorsa Sadat, Larouche, Valérie, Tabori, Uri, Hawkins, Cynthia, Ellezam, Benjamin, Décarie, Jean-Claude, Théoret, Yves, Métras, Marie-Élaine, McKeown, Tara, Ospina, Luis H., Vairy, Stéphanie, Ramaswamy, Vijay, Coltin, Hallie, Sultan, Serge, Legault, Geneviève, Bouffet, Éric, Lafay-Cousin, Lucie, Hukin, Juliette, Erker, Craig, Caru, Maxime, Dehaes, Mathieu, Jabado, Nada, Perreault, Sébastien, and Lippé, Sarah

Published
2024
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4. Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function

Author

Andrade, Augusto Faria, Annett, Alva, Karimi, Elham, Topouza, Danai Georgia, Rezanejad, Morteza, Liu, Yitong, McNicholas, Michael, Gonzalez Santiago, Eduardo G., Llivichuzhca-Loja, Dhana, Gehlhaar, Arne, Jessa, Selin, De Cola, Antonella, Chandarana, Bhavyaa, Russo, Caterina, Faury, Damien, Danieau, Geoffroy, Puligandla, Evan, Wei, Yuhong, Zeinieh, Michele, Wu, Qing, Hebert, Steven, Juretic, Nikoleta, Nakada, Emily M., Krug, Brian, Larouche, Valerie, Weil, Alexander G., Dudley, Roy W. R., Karamchandani, Jason, Agnihotri, Sameer, Quail, Daniela F., Ellezam, Benjamin, Konnikova, Liza, Walsh, Logan A., Pathania, Manav, Kleinman, Claudia L., and Jabado, Nada

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

Author

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

Published
2024
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6. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

Author

Kilburn, Lindsay B., Khuong-Quang, Dong-Anh, Hansford, Jordan R., Landi, Daniel, van der Lugt, Jasper, Leary, Sarah E. S., Driever, Pablo Hernáiz, Bailey, Simon, Perreault, Sébastien, McCowage, Geoffrey, Waanders, Angela J., Ziegler, David S., Witt, Olaf, Baxter, Patricia A., Kang, Hyoung Jin, Hassall, Timothy E., Han, Jung Woo, Hargrave, Darren, Franson, Andrea T., Yalon Oren, Michal, Toledano, Helen, Larouche, Valérie, Kline, Cassie, Abdelbaki, Mohamed S., Jabado, Nada, Gottardo, Nicholas G., Gerber, Nicolas U., Whipple, Nicholas S., Segal, Devorah, Chi, Susan N., Oren, Liat, Tan, Enrica E. K., Mueller, Sabine, Cornelio, Izzy, McLeod, Lisa, Zhao, Xin, Walter, Ashley, Da Costa, Daniel, Manley, Peter, Blackman, Samuel C., Packer, Roger J., and Nysom, Karsten

Published
2024
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7. Author Correction: The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

Author

Kilburn, Lindsay B., Khuong-Quang, Dong-Anh, Hansford, Jordan R., Landi, Daniel, van der Lugt, Jasper, Leary, Sarah E. S., Driever, Pablo Hernáiz, Bailey, Simon, Perreault, Sébastien, McCowage, Geoffrey, Waanders, Angela J., Ziegler, David S., Witt, Olaf, Baxter, Patricia A., Kang, Hyoung Jin, Hassall, Timothy E., Han, Jung Woo, Hargrave, Darren, Franson, Andrea T., Yalon Oren, Michal, Toledano, Helen, Larouche, Valérie, Kline, Cassie, Abdelbaki, Mohamed S., Jabado, Nada, Gottardo, Nicholas G., Gerber, Nicolas U., Whipple, Nicholas S., Segal, Devorah, Chi, Susan N., Oren, Liat, Tan, Enrica E. K., Mueller, Sabine, Cornelio, Izzy, McLeod, Lisa, Zhao, Xin, Walter, Ashley, Da Costa, Daniel, Manley, Peter, Blackman, Samuel C., Packer, Roger J., and Nysom, Karsten

Published
2024
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8. TULIPs decorate the three-dimensional genome of PFA ependymoma

Author

Johnston, Michael J., Lee, John J.Y., Hu, Bo, Nikolic, Ana, Hasheminasabgorji, Elham, Baguette, Audrey, Paik, Seungil, Chen, Haifen, Kumar, Sachin, Chen, Carol C.L., Jessa, Selin, Balin, Polina, Fong, Vernon, Zwaig, Melissa, Michealraj, Kulandaimanuvel Antony, Chen, Xun, Zhang, Yanlin, Varadharajan, Srinidhi, Billon, Pierre, Juretic, Nikoleta, Daniels, Craig, Rao, Amulya Nageswara, Giannini, Caterina, Thompson, Eric M., Garami, Miklos, Hauser, Peter, Pocza, Timea, Ra, Young Shin, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Lee, Ji Yeoun, Grajkowska, Wieslawa, Perek-Polnik, Marta, Agnihotri, Sameer, Mack, Stephen, Ellezam, Benjamin, Weil, Alex, Rich, Jeremy, Bourque, Guillaume, Chan, Jennifer A., Yong, V. Wee, Lupien, Mathieu, Ragoussis, Jiannis, Kleinman, Claudia, Majewski, Jacek, Blanchette, Mathieu, Jabado, Nada, Taylor, Michael D., and Gallo, Marco

Published
2024
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9. Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma

Author

Visvanathan, Abhirami, Saulnier, Olivier, Chen, Chuan, Haldipur, Parthiv, Orisme, Wilda, Delaidelli, Alberto, Shin, Seungmin, Millman, Jake, Bryant, Andrew, Abeysundara, Namal, Wu, Xujia, Hendrikse, Liam D., Patil, Vikas, Bashardanesh, Zahedeh, Golser, Joseph, Livingston, Bryn G., Nakashima, Takuma, Funakoshi, Yusuke, Ong, Winnie, Rasnitsyn, Alexandra, Aldinger, Kimberly A., Richman, Cory M., Van Ommeren, Randy, Lee, John J.Y., Ly, Michelle, Vladoiu, Maria C., Kharas, Kaitlin, Balin, Polina, Erickson, Anders W., Fong, Vernon, Zhang, Jiao, Suárez, Raúl A., Wang, Hao, Huang, Ning, Pallota, Jonelle G., Douglas, Tajana, Haapasalo, Joonas, Razavi, Ferechte, Silvestri, Evelina, Sirbu, Olga, Worme, Samantha, Kameda-Smith, Michelle M., Wu, Xiaochong, Daniels, Craig, MichaelRaj, Antony K., Bhaduri, Aparna, Schramek, Daniel, Suzuki, Hiromichi, Garzia, Livia, Ahmed, Nabil, Kleinman, Claudia L., Stein, Lincoln D., Dirks, Peter, Dunham, Christopher, Jabado, Nada, Rich, Jeremy N., Li, Wei, Sorensen, Poul H., Wechsler-Reya, Robert J., Weiss, William A., Millen, Kathleen J., Ellison, David W., Dimitrov, Dimiter S., and Taylor, Michael D.

Published
2024
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11. MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas

Author

Sigaud, Romain, Albert, Thomas K., Hess, Caroline, Hielscher, Thomas, Winkler, Nadine, Kocher, Daniela, Walter, Carolin, Münter, Daniel, Selt, Florian, Usta, Diren, Ecker, Jonas, Brentrup, Angela, Hasselblatt, Martin, Thomas, Christian, Varghese, Julian, Capper, David, Thomale, Ulrich W., Hernáiz Driever, Pablo, Simon, Michèle, Horn, Svea, Herz, Nina Annika, Koch, Arend, Sahm, Felix, Hamelmann, Stefan, Faria-Andrade, Augusto, Jabado, Nada, Schuhmann, Martin U., Schouten-van Meeteren, Antoinette Y. N., Hoving, Eelco, Brummer, Tilman, van Tilburg, Cornelis M., Pfister, Stefan M., Witt, Olaf, Jones, David T. W., Kerl, Kornelius, and Milde, Till

Published
2023
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12. Comprehensive Genomic Analysis of Cemento-Ossifying Fibroma

Author

Gomez, Ricardo Santiago, El Mouatani, Ahmed, Duarte-Andrade, Filipe Fideles, Pereira, Thais dos Santos Fontes, Guimarães, Letícia Martins, Gayden, Tenzin, Faury, Damien, Nakada, Emily M., Langlois, Sylvie, Sinnett, Daniel, de Castro, Wagner Henriques, Diniz, Marina Gonçalves, Jabado, Nada, and Gomes, Carolina Cavalieri

Published
2024
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13. Using comprehensive genomic and functional analyses for resolving genotype–phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study

Author

Hamideh, Dima, Das, Anirban, Bianchi, Vanessa, Chung, Jiil, Negm, Logine, Levine, Adrian, Basbous, Maya, Sanchez-Ramirez, Santiago, Mikael, Leonie, Jabado, Nada, Atweh, Lamya, Lteif, Mireille, Mahfouz, Rami, Tarek, Nidale, Abboud, Miguel, Muwakkit, Samar, Hawkins, Cynthia, Tabori, Uri, and Saab, Raya

Published
2023
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14. The transcriptional landscape of Shh medulloblastoma.

Author

Skowron, Patryk, Farooq, Hamza, Cavalli, Florence MG, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John JY, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D

Subjects
Humans, Medulloblastoma, Cerebellar Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Hedgehog Proteins, Gene Regulatory Networks, Genetic Variation, Young Adult, Transcriptome, Pediatric Research Initiative, Brain Cancer, Pediatric, Rare Diseases, Genetics, Pediatric Cancer, Clinical Research, Brain Disorders, Neurosciences, Biotechnology, Human Genome, Cancer, 2.1 Biological and endogenous factors
Abstract

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Published
2021

15. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

Author

Kumar, Rahul, Smith, Kyle, Deng, Maximilian, Terhune, Colt, Robinson, Giles, Orr, Brent, Liu, Anthony, Lin, Tong, Billups, Catherine, Chintagumpala, Murali, Bowers, Daniel, Hassall, Timothy, Hansford, Jordan, Khuong-Quang, Dong, Crawford, John, Bendel, Anne, Gururangan, Sridharan, Schroeder, Kristin, Bouffet, Eric, Bartels, Ute, Fisher, Michael, Cohn, Richard, Partap, Sonia, Kellie, Stewart, McCowage, Geoffrey, Paulino, Arnold, Rutkowski, Stefan, Fleischhack, Gudrun, Dhall, Girish, Klesse, Laura, Leary, Sarah, Nazarian, Javad, Kool, Marcel, Wesseling, Pieter, Ryzhova, Marina, Zheludkova, Olga, Golanov, Andrey, McLendon, Roger, Packer, Roger, Dunham, Christopher, Hukin, Juliette, Fouladi, Maryam, Faria, Claudia, Pimentel, Jose, Walter, Andrew, Jabado, Nada, Cho, Yoon-Jae, Perreault, Sebastien, Croul, Sidney, Zapotocky, Michal, Hawkins, Cynthia, Tabori, Uri, Taylor, Michael, Pfister, Stefan, Klimo, Paul, Boop, Frederick, Ellison, David, Merchant, Thomas, Onar-Thomas, Arzu, Korshunov, Andrey, Jones, David, Gajjar, Amar, Ramaswamy, Vijay, and Northcott, Paul

Subjects
Biomarkers, Tumor, Cerebellar Neoplasms, Child, Child, Preschool, Clinical Trials as Topic, DNA Methylation, Disease Progression, Epigenome, Epigenomics, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Medulloblastoma, Neoplasm Recurrence, Local, Retreatment, Time Factors, Treatment Outcome
Abstract

PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Published
2021

16. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.

Author

Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Reuss, David E, Sturm, Dominik, Hench, Jürgen, Frank, Stephan, Krskova, Lenka, Vicha, Ales, Zapotocky, Michal, Bison, Brigitte, Castel, David, Grill, Jacques, Debily, Marie-Anne, Harter, Patrick N, Snuderl, Matija, Kramm, Christof M, Reifenberger, Guido, Korshunov, Andrey, Jabado, Nada, Wesseling, Pieter, Wick, Wolfgang, Solomon, David A, Perry, Arie, Jacques, Thomas S, Jones, Chris, Witt, Olaf, Pfister, Stefan M, von Deimling, Andreas, Jones, David TW, and Sahm, Felix

Subjects
Brain Disorders, Pediatric Cancer, Cancer, Pediatric, Brain Cancer, Rare Diseases, Genetics, Neurosciences, Brain Neoplasms, Child, DNA Methylation, ErbB Receptors, Genes, erbB-1, Glioma, Histones, Humans, Mutation, Thalamus, (bi)thalamic, EGFR mutation, H3 K27M mutation, K27me3, pediatric-type high-grade glioma, EGFR mutation, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundMalignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern.MethodsHere, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas.ResultsEGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations.ConclusionsOur findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.

Published
2021

17. K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas

Author

Jessa, Selin, Mohammadnia, Abdulshakour, Harutyunyan, Ashot S., Hulswit, Maud, Varadharajan, Srinidhi, Lakkis, Hussein, Kabir, Nisha, Bashardanesh, Zahedeh, Hébert, Steven, Faury, Damien, Vladoiu, Maria C., Worme, Samantha, Coutelier, Marie, Krug, Brian, Faria Andrade, Augusto, Pathania, Manav, Bajic, Andrea, Weil, Alexander G., Ellezam, Benjamin, Atkinson, Jeffrey, Dudley, Roy W. R., Farmer, Jean-Pierre, Perreault, Sebastien, Garcia, Benjamin A., Larouche, Valérie, Blanchette, Mathieu, Garzia, Livia, Bhaduri, Aparna, Ligon, Keith L., Bandopadhayay, Pratiti, Taylor, Michael D., Mack, Stephen C., Jabado, Nada, and Kleinman, Claudia L.

Published
2022
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19. Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Author

Balakrishnan, Ilango, Danis, Etienne, Pierce, Angela, Madhavan, Krishna, Wang, Dong, Dahl, Nathan, Sanford, Bridget, Birks, Diane K, Davidson, Nate, Metselaar, Dennis S, Meel, Michaël Hananja, Lemma, Rakeb, Donson, Andrew, Vijmasi, Trinka, Katagi, Hiroaki, Sola, Ismail, Fosmire, Susan, Alimova, Irina, Steiner, Jenna, Gilani, Ahmed, Hulleman, Esther, Serkova, Natalie J, Hashizume, Rintaro, Hawkins, Cynthia, Carcaboso, Angel M, Gupta, Nalin, Monje, Michelle, Jabado, Nada, Jones, Kenneth, Foreman, Nicholas, Green, Adam, Vibhakar, Rajeev, and Venkataraman, Sujatha

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Genetics, Stem Cell Research, Biotechnology, Cancer, Brain Disorders, Stem Cell Research - Nonembryonic - Non-Human, Brain Cancer, Aging, Astrocytoma, Brain Stem Neoplasms, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Child, Child, Preschool, Chromatin, Diffuse Intrinsic Pontine Glioma, Epigenomics, Female, Glioma, Histones, Humans, Lysine, Male, Mutation, Neoplasm Recurrence, Local, Polycomb Repressive Complex 1, BH3 mimetics, BMI1, DIPG, H3K27M mutant, H3WT, PTC 028, RNAi screen, SASP, senescence, Bmi1, PTC028, Medical Physiology, Biological sciences
Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.

Published
2020

20. Epigenomic programming in early fetal brain development

Author

Li, Luolan, Maire, Cecile L, Bilenky, Misha, Carles, Annaïck, Heravi-Moussavi, Alireza, Hong, Chibo, Tam, Angela, Kamoh, Baljit, Cho, Stephanie, Cheung, Dorothy, Li, Irene, Wong, Tina, Nagarajan, Raman P, Mungall, Andrew J, Moore, Richard, Wang, Ting, Kleinman, Claudia L, Jabado, Nada, Jones, Steven JM, Marra, Marco A, Ligon, Keith L, Costello, Joseph F, and Hirst, Martin

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Stem Cell Research, Clinical Research, Neurosciences, Stem Cell Research - Nonembryonic - Non-Human, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Brain, Epigenesis, Genetic, Epigenome, Female, Fetus, Gene Expression Regulation, Developmental, Humans, Neural Stem Cells, Pregnancy, Transcriptome, Twins, brain, cortex, DNA methylation, enhancer, epigenetics, fetal, ganglionic eminence, gestational week, neural progenitor cells, transcriptional network, Clinical Sciences
Abstract

Aim: To provide a comprehensive understanding of gene regulatory networks in the developing human brain and a foundation for interpreting pathogenic deregulation. Materials & methods: We generated reference epigenomes and transcriptomes of dissected brain regions and primary neural progenitor cells (NPCs) derived from cortical and ganglionic eminence tissues of four normal human fetuses. Results: Integration of these data across developmental stages revealed a directional increase in active regulatory states, transcription factor activities and gene transcription with developmental stage. Consistent with differences in their biology, NPCs derived from cortical and ganglionic eminence regions contained common, region specific, and gestational week specific regulatory states. Conclusion: We provide a high-resolution regulatory network for NPCs from different brain regions as a comprehensive reference for future studies.

Published
2020

21. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Hendrikse, Liam D., Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H., Erickson, Anders W., Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L., Shokouhian, Mohammad, Suárez, Raúl A., Ly, Michelle, Borlase, Stephanie, Scott, David S., Vladoiu, Maria C., Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J. Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y., Kumar, Sachin A., Balin, Polina, Visvanathan, Abhirami, Lee, John J. Y., Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L., Luu, Betty, Bérubé, Pierre, Wang, Yu C., Pfister, Stefan M., Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A., Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J., Kros, Johan M., Zitterbart, Karel, Bailey, Swneke D., Eberhart, Charles G., Rao, Amulya A. N., Giannini, Caterina, Olson, James M., Garami, Miklós, Hauser, Peter, Phillips, Joanna J., Ra, Young S., de Torres, Carmen, Mora, Jaume, Li, Kay K. W., Ng, Ho-Keung, Poon, Wai S., Pollack, Ian F., López-Aguilar, Enrique, Gillespie, G. Yancey, Van Meter, Timothy E., Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C., Cooper, Michael K., Rubin, Joshua B., Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S., Van Meir, Erwin G., Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G., Faria, Claudia C., Roussel, Martine F., Boop, Frederick, Chan, Jennifer A., Aldinger, Kimberly A., Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E., Thompson, Eric M., Ansari, Marc, Garre, Maria L., Chico, Fernando, Eguía, Pilar, Pérezpeña, Mario, Morrissy, A. Sorana, Cavalli, Florence M. G., Wu, Xiaochong, Daniels, Craig, Rich, Jeremy N., Jones, Steven J. M., Moore, Richard A., Marra, Marco A., Huang, Xi, Reimand, Jüri, Sorensen, Poul H., Wechsler-Reya, Robert J., Weiss, William A., Pugh, Trevor J., Garzia, Livia, Kleinman, Claudia L., Stein, Lincoln D., Jabado, Nada, Malkin, David, Ayrault, Olivier, Golden, Jeffrey A., Ellison, David W., Doble, Brad, Ramaswamy, Vijay, Werbowetski-Ogilvie, Tamra E., Suzuki, Hiromichi, Millen, Kathleen J., and Taylor, Michael D.

Published
2022
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22. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma

Author

Dubois, Frank P. B., Shapira, Ofer, Greenwald, Noah F., Zack, Travis, Wala, Jeremiah, Tsai, Jessica W., Crane, Alexander, Baguette, Audrey, Hadjadj, Djihad, Harutyunyan, Ashot S., Kumar, Kiran H., Blattner-Johnson, Mirjam, Vogelzang, Jayne, Sousa, Cecilia, Kang, Kyung Shin, Sinai, Claire, Wang, Dayle K., Khadka, Prasidda, Lewis, Kathleen, Nguyen, Lan, Malkin, Hayley, Ho, Patricia, O’Rourke, Ryan, Zhang, Shu, Gold, Rose, Deng, Davy, Serrano, Jonathan, Snuderl, Matija, Jones, Chris, Wright, Karen D., Chi, Susan N., Grill, Jacques, Kleinman, Claudia L., Goumnerova, Liliana C., Jabado, Nada, Jones, David T. W., Kieran, Mark W., Ligon, Keith L., Beroukhim, Rameen, and Bandopadhayay, Pratiti

Published
2022
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24. Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome

Author

Golbourn, Brian J., Halbert, Matthew E., Halligan, Katharine, Varadharajan, Srinidhi, Krug, Brian, Mbah, Nneka E., Kabir, Nisha, Stanton, Ann-Catherine J., Locke, Abigail L., Casillo, Stephanie M., Zhao, Yanhua, Sanders, Lauren M., Cheney, Allison, Mullett, Steven J., Chen, Apeng, Wassell, Michelle, Andren, Anthony, Perez, Jennifer, Jane, Esther P., Premkumar, Daniel R. David, Koncar, Robert F., Mirhadi, Shideh, McCarl, Lauren H., Chang, Yue-Fang, Wu, Yijen L., Gatesman, Taylor A., Cruz, Andrea F., Zapotocky, Michal, Hu, Baoli, Kohanbash, Gary, Wang, Xiuxing, Vartanian, Alenoush, Moran, Michael F., Lieberman, Frank, Amankulor, Nduka M., Wendell, Stacy G., Vaske, Olena M., Panigrahy, Ashok, Felker, James, Bertrand, Kelsey C., Kleinman, Claudia L., Rich, Jeremy N., Friedlander, Robert M., Broniscer, Alberto, Lyssiotis, Costas, Jabado, Nada, Pollack, Ian F., Mack, Stephen C., and Agnihotri, Sameer

Published
2022
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25. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Author

Sin-Chan, Patrick, Mumal, Iqra, Suwal, Tannu, Ho, Ben, Fan, Xiaolian, Singh, Irtisha, Du, Yuchen, Lu, Mei, Patel, Neilket, Torchia, Jonathon, Popovski, Dean, Fouladi, Maryam, Guilhamon, Paul, Hansford, Jordan R, Leary, Sarah, Hoffman, Lindsey M, Levy, Jean M Mulcahy, Lassaletta, Alvaro, Solano-Paez, Palma, Rivas, Eloy, Reddy, Alyssa, Gillespie, G Yancey, Gupta, Nalin, Van Meter, Timothy E, Nakamura, Hideo, Wong, Tai-Tong, Ra, Young-Shin, Kim, Seung-Ki, Massimi, Luca, Grundy, Richard G, Fangusaro, Jason, Johnston, Donna, Chan, Jennifer, Lafay-Cousin, Lucie, Hwang, Eugene I, Wang, Yin, Catchpoole, Daniel, Michaud, Jean, Ellezam, Benjamin, Ramanujachar, Ramya, Lindsay, Holly, Taylor, Michael D, Hawkins, Cynthia E, Bouffet, Eric, Jabado, Nada, Singh, Sheila K, Kleinman, Claudia L, Barsyte-Lovejoy, Dalia, Li, Xiao-Nan, Dirks, Peter B, Lin, Charles Y, Mack, Stephen C, Rich, Jeremy N, and Huang, Annie

Subjects
Rare Diseases, Neurosciences, Cancer, Genetics, Biotechnology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biomarkers, Tumor, Brain Neoplasms, Cell Cycle, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 2, DNA Copy Number Variations, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, MicroRNAs, Models, Biological, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Germ Cell and Embryonal, Oncogenes, RNA-Binding Proteins, C19MC, ETMR, LIN28A, MYCN, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Published
2019

26. Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data

Author

Zwaig, Melissa, Baguette, Audrey, Hu, Bo, Johnston, Michael, Lakkis, Hussein, Nakada, Emily M., Faury, Damien, Juretic, Nikoleta, Ellezam, Benjamin, Weil, Alexandre G., Karamchandani, Jason, Majewski, Jacek, Blanchette, Mathieu, Taylor, Michael D., Gallo, Marco, Kleinman, Claudia L., Jabado, Nada, and Ragoussis, Jiannis

Published
2022
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27. Whole‐exome sequencing and copy number alterations analysis in a case of expansive florid cemento‐osseous dysplasia.

Author

Gomes, Carolina Cavaliéri, Bastos, Victor Coutinho, El Mouatani, Ahmed, Duarte‐Andrade, Filipe Fideles, Jabado, Nada, de Castro, Wagner Henriques, and Gomez, Ricardo Santiago

Subjects
SOMATIC mutation, DYSPLASIA, GENETIC variation, MANDIBLE, GENETICS
Abstract

Key Clinical Message: Whole‐exome sequencing (WES) analysis of an expansive case florid cemento‐osseus dysplasia were reported for the first time. Also, the new potential candidate genes were reported to expand our knowledge about their molecular pathogenesis. We report a case of expansive florid cemento‐osseus dysplasia in a 32‐year‐old female patient who presented an expansive tumoral lesion in the anterior mandible. As florid cemento‐osseus dysplasia have only been molecularly investigated using targeted‐sequencing, fragments of the lesion were collected and subjected to molecular investigation using WES to assess somatic mutations as well as copy number alterations. No gains and losses of chromosomal arms or segments longer than 1 Mb were detected. Our findings revealed a pathogenic stopgain variant at the KIF5C gene, a stoploss variant at MAPK10, and missense SNV at COL6A2 at DCDC1, suggesting potential candidate genes associated with florid cemento‐osseus dysplasia. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Author

Waszak, Sebastian M, Northcott, Paul A, Buchhalter, Ivo, Robinson, Giles W, Sutter, Christian, Groebner, Susanne, Grund, Kerstin B, Brugières, Laurence, Jones, David TW, Pajtler, Kristian W, Morrissy, A Sorana, Kool, Marcel, Sturm, Dominik, Chavez, Lukas, Ernst, Aurelie, Brabetz, Sebastian, Hain, Michael, Zichner, Thomas, Segura-Wang, Maia, Weischenfeldt, Joachim, Rausch, Tobias, Mardin, Balca R, Zhou, Xin, Baciu, Cristina, Lawerenz, Christian, Chan, Jennifer A, Varlet, Pascale, Guerrini-Rousseau, Lea, Fults, Daniel W, Grajkowska, Wiesława, Hauser, Peter, Jabado, Nada, Ra, Young-Shin, Zitterbart, Karel, Shringarpure, Suyash S, De La Vega, Francisco M, Bustamante, Carlos D, Ng, Ho-Keung, Perry, Arie, MacDonald, Tobey J, Hernáiz Driever, Pablo, Bendel, Anne E, Bowers, Daniel C, McCowage, Geoffrey, Chintagumpala, Murali M, Cohn, Richard, Hassall, Timothy, Fleischhack, Gudrun, Eggen, Tone, Wesenberg, Finn, Feychting, Maria, Lannering, Birgitta, Schüz, Joachim, Johansen, Christoffer, Andersen, Tina V, Röösli, Martin, Kuehni, Claudia E, Grotzer, Michael, Kjaerheim, Kristina, Monoranu, Camelia M, Archer, Tenley C, Duke, Elizabeth, Pomeroy, Scott L, Shelagh, Redmond, Frank, Stephan, Sumerauer, David, Scheurlen, Wolfram, Ryzhova, Marina V, Milde, Till, Kratz, Christian P, Samuel, David, Zhang, Jinghui, Solomon, David A, Marra, Marco, Eils, Roland, Bartram, Claus R, von Hoff, Katja, Rutkowski, Stefan, Ramaswamy, Vijay, Gilbertson, Richard J, Korshunov, Andrey, Taylor, Michael D, Lichter, Peter, Malkin, David, Gajjar, Amar, Korbel, Jan O, and Pfister, Stefan M

Subjects
Humans, Medulloblastoma, Cerebellar Neoplasms, Genetic Predisposition to Disease, Risk Factors, Retrospective Studies, Prospective Studies, Reproducibility of Results, Predictive Value of Tests, Gene Expression Profiling, Pedigree, DNA Mutational Analysis, DNA Methylation, Heredity, Phenotype, Germ-Line Mutation, Models, Genetic, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Young Adult, Genetic Testing, Transcriptome, Biomarkers, Tumor, Progression-Free Survival, Exome Sequencing, Brain Cancer, Genetics, Cancer, Human Genome, Pediatric, Pediatric Cancer, Rare Diseases, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundMedulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.MethodsIn this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.FindingsWe included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.InterpretationGenetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.FundingGerman Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

Published
2018

30. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

Author

Garzia, Livia, Kijima, Noriyuki, Morrissy, A Sorana, De Antonellis, Pasqualino, Guerreiro-Stucklin, Ana, Holgado, Borja L, Wu, Xiaochong, Wang, Xin, Parsons, Michael, Zayne, Kory, Manno, Alex, Kuzan-Fischer, Claudia, Nor, Carolina, Donovan, Laura K, Liu, Jessica, Qin, Lei, Garancher, Alexandra, Liu, Kun-Wei, Mansouri, Sheila, Luu, Betty, Thompson, Yuan Yao, Ramaswamy, Vijay, Peacock, John, Farooq, Hamza, Skowron, Patryk, Shih, David JH, Li, Angela, Ensan, Sherine, Robbins, Clinton S, Cybulsky, Myron, Mitra, Siddhartha, Ma, Yussanne, Moore, Richard, Mungall, Andy, Cho, Yoon-Jae, Weiss, William A, Chan, Jennifer A, Hawkins, Cynthia E, Massimino, Maura, Jabado, Nada, Zapotocky, Michal, Sumerauer, David, Bouffet, Eric, Dirks, Peter, Tabori, Uri, Sorensen, Poul HB, Brastianos, Priscilla K, Aldape, Kenneth, Jones, Steven JM, Marra, Marco A, Woodgett, James R, Wechsler-Reya, Robert J, Fults, Daniel W, and Taylor, Michael D

Subjects
Brain Cancer, Cancer, Neurosciences, Pediatric Cancer, Pediatric, Rare Diseases, Brain Disorders, Allografts, Animals, Cell Line, Tumor, Chemokine CCL2, Chromosomes, Human, Pair 10, Female, Humans, Male, Medulloblastoma, Meningeal Neoplasms, Mice, SCID, Neoplastic Cells, Circulating, Parabiosis, brain tumors, circulating tumor cells, medulloblastoma, metastases, pediatric cancer, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Published
2018

31. Pediatric low-grade gliomas: next biologically driven steps.

Author

Jones, David TW, Kieran, Mark W, Bouffet, Eric, Alexandrescu, Sanda, Bandopadhayay, Pratiti, Bornhorst, Miriam, Ellison, David, Fangusaro, Jason, Fisher, Michael J, Foreman, Nicholas, Fouladi, Maryam, Hargrave, Darren, Hawkins, Cynthia, Jabado, Nada, Massimino, Maura, Mueller, Sabine, Perilongo, Giorgio, Schouten van Meeteren, Antoinette YN, Tabori, Uri, Warren, Katherine, Waanders, Angela J, Walker, David, Weiss, William, Witt, Olaf, Wright, Karen, Zhu, Yuan, Bowers, Daniel C, Pfister, Stefan M, and Packer, Roger J

Subjects
Pediatric, Brain Disorders, Neurosciences, Pediatric Research Initiative, Cancer, Rare Diseases, Brain Cancer, Adult, Animals, Brain Neoplasms, Child, Disease Models, Animal, Glioma, Humans, Neoplasm Grading, Pathology, Molecular, Treatment Outcome, low-grade glioma, MAPK pathway, molecular diagnostics, neurooncology, pediatric brain tumor, targeted therapy, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.

Published
2018

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

Author

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

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

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

Published
2017

34. Abstract B045: Adaptive purine metabolism drives radiation therapy resistance in H3K27M-diffuse midline glioma

Author

Peterson, Erik R., primary, Sajjakulnukit, Peter, additional, Scott, Andrew, additional, Heaslip, Caleb, additional, Andren, Anthony, additional, Wilder-Romans, Kari, additional, Lin, Angelica, additional, Obrien, Alexandra, additional, Zhao, Zitong, additional, Zhang, Li, additional, Venneti, Sriram, additional, Koschmann, Carl, additional, Jabado, Nada, additional, Castro, Maria G., additional, and Wahl, Daniel R., additional

Published
2024
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35. Abstract B035: A compendium of syngeneic, transplantable pediatric high-grade glioma models reveals subtype-specific therapeutic vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, additional, Bashardanesh, Zahedeh, additional, Foss, Amelia, additional, Lloyd, Cameron, additional, Hebert, Steven, additional, Faury, Damien, additional, Andrade, Augusto Faria, additional, Jabado, Nada, additional, Kleinman, Claudia, additional, and Pathania, Manav, additional

Published
2024
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36. Figure 6 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, primary, Bashardanesh, Zahedeh, primary, Foss, Amelia, primary, Lloyd, Cameron B., primary, Hébert, Steven, primary, Faury, Damien, primary, Andrade, Augusto Faria, primary, Jabado, Nada, primary, Kleinman, Claudia L., primary, and Pathania, Manav, primary

Published
2024
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37. Supplementary Table 6 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, primary, Bashardanesh, Zahedeh, primary, Foss, Amelia, primary, Lloyd, Cameron B., primary, Hébert, Steven, primary, Faury, Damien, primary, Andrade, Augusto Faria, primary, Jabado, Nada, primary, Kleinman, Claudia L., primary, and Pathania, Manav, primary

Published
2024
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38. Data from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, primary, Bashardanesh, Zahedeh, primary, Foss, Amelia, primary, Lloyd, Cameron B., primary, Hébert, Steven, primary, Faury, Damien, primary, Andrade, Augusto Faria, primary, Jabado, Nada, primary, Kleinman, Claudia L., primary, and Pathania, Manav, primary

Published
2024
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39. Supplementary Table 5 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, primary, Bashardanesh, Zahedeh, primary, Foss, Amelia, primary, Lloyd, Cameron B., primary, Hébert, Steven, primary, Faury, Damien, primary, Andrade, Augusto Faria, primary, Jabado, Nada, primary, Kleinman, Claudia L., primary, and Pathania, Manav, primary

Published
2024
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40. Supplementary Tables 1-3, 7-9 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, primary, Bashardanesh, Zahedeh, primary, Foss, Amelia, primary, Lloyd, Cameron B., primary, Hébert, Steven, primary, Faury, Damien, primary, Andrade, Augusto Faria, primary, Jabado, Nada, primary, Kleinman, Claudia L., primary, and Pathania, Manav, primary

Published
2024
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41. Supplementary Table 4 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, primary, Bashardanesh, Zahedeh, primary, Foss, Amelia, primary, Lloyd, Cameron B., primary, Hébert, Steven, primary, Faury, Damien, primary, Andrade, Augusto Faria, primary, Jabado, Nada, primary, Kleinman, Claudia L., primary, and Pathania, Manav, primary

Published
2024
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42. Supplementary Figures 1-27 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

Author

McNicholas, Michael, primary, De Cola, Antonella, primary, Bashardanesh, Zahedeh, primary, Foss, Amelia, primary, Lloyd, Cameron B., primary, Hébert, Steven, primary, Faury, Damien, primary, Andrade, Augusto Faria, primary, Jabado, Nada, primary, Kleinman, Claudia L., primary, and Pathania, Manav, primary

Published
2024
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43. Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors

Author

Pathak, Rajiv, Zin, Francesca, Thomas, Christian, Bens, Susanne, Gayden, Tenzin, Karamchandani, Jason, Dudley, Roy W., Nemes, Karolina, Johann, Pascal D., Oyen, Florian, Kordes, Uwe, Jabado, Nada, Siebert, Reiner, Paulus, Werner, Kool, Marcel, Frühwald, Michael C., Albrecht, Steffen, Kalpana, Ganjam V., and Hasselblatt, Martin

Published
2021
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44. Glioblastoma cell populations with distinct oncogenic programs release podoplanin as procoagulant extracellular vesicles

Author

Tawil, Nadim, Bassawon, Rayhaan, Meehan, Brian, Nehme, Ali, Montermini, Laura, Gayden, Tenzin, De Jay, Nicolas, Spinelli, Cristiana, Chennakrishnaiah, Shilpa, Choi, Dongsic, Adnani, Lata, Zeinieh, Michele, Jabado, Nada, Kleinman, Claudia L., Witcher, Michael, Riazalhosseini, Yasser, Key, Nigel S., Schiff, David, Grover, Steven P., Mackman, Nigel, Couturier, Charles P., Petrecca, Kevin, Suvà, Mario L., Patel, Anoop, Tirosh, Itay, Najafabadi, Hamed, and Rak, Janusz

Published
2021
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45. The whole-genome landscape of medulloblastoma subtypes

Author

Northcott, Paul A, Buchhalter, Ivo, Morrissy, A Sorana, Hovestadt, Volker, Weischenfeldt, Joachim, Ehrenberger, Tobias, Gröbner, Susanne, Segura-Wang, Maia, Zichner, Thomas, Rudneva, Vasilisa A, Warnatz, Hans-Jörg, Sidiropoulos, Nikos, Phillips, Aaron H, Schumacher, Steven, Kleinheinz, Kortine, Waszak, Sebastian M, Erkek, Serap, Jones, David TW, Worst, Barbara C, Kool, Marcel, Zapatka, Marc, Jäger, Natalie, Chavez, Lukas, Hutter, Barbara, Bieg, Matthias, Paramasivam, Nagarajan, Heinold, Michael, Gu, Zuguang, Ishaque, Naveed, Jäger-Schmidt, Christina, Imbusch, Charles D, Jugold, Alke, Hübschmann, Daniel, Risch, Thomas, Amstislavskiy, Vyacheslav, Gonzalez, Francisco German Rodriguez, Weber, Ursula D, Wolf, Stephan, Robinson, Giles W, Zhou, Xin, Wu, Gang, Finkelstein, David, Liu, Yanling, Cavalli, Florence MG, Luu, Betty, Ramaswamy, Vijay, Wu, Xiaochong, Koster, Jan, Ryzhova, Marina, Cho, Yoon-Jae, Pomeroy, Scott L, Herold-Mende, Christel, Schuhmann, Martin, Ebinger, Martin, Liau, Linda M, Mora, Jaume, McLendon, Roger E, Jabado, Nada, Kumabe, Toshihiro, Chuah, Eric, Ma, Yussanne, Moore, Richard A, Mungall, Andrew J, Mungall, Karen L, Thiessen, Nina, Tse, Kane, Wong, Tina, Jones, Steven JM, Witt, Olaf, Milde, Till, Von Deimling, Andreas, Capper, David, Korshunov, Andrey, Yaspo, Marie-Laure, Kriwacki, Richard, Gajjar, Amar, Zhang, Jinghui, Beroukhim, Rameen, Fraenkel, Ernest, Korbel, Jan O, Brors, Benedikt, Schlesner, Matthias, Eils, Roland, Marra, Marco A, Pfister, Stefan M, Taylor, Michael D, and Lichter, Peter

Subjects
Cancer, Human Genome, Brain Disorders, Pediatric Cancer, Brain Cancer, Genetics, Biotechnology, Rare Diseases, Neurosciences, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Carcinogenesis, Carrier Proteins, Cohort Studies, DNA Methylation, DNA Mutational Analysis, Datasets as Topic, Epistasis, Genetic, Genome, Human, Genomics, Humans, Medulloblastoma, Molecular Targeted Therapy, Muscle Proteins, Mutation, Oncogenes, Transcription Factors, Whole Genome Sequencing, Wnt Proteins, General Science & Technology
Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Published
2017

46. Pediatric low-grade gliomas: implications of the biologic era

Author

Packer, Roger J, Pfister, Stephan, Bouffet, Eric, Avery, Robert, Bandopadhayay, Pratiti, Bornhorst, Miriam, Bowers, Daniel C, Ellison, David, Fangusaro, Jason, Foreman, Nicholas, Fouladi, Maryam, Gajjar, Amar, Haas-Kogan, Daphne, Hawkins, Cynthia, Ho, Cheng-Ying, Hwang, Eugene, Jabado, Nada, Kilburn, Lindsay B, Lassaletta, Alvaro, Ligon, Keith L, Massimino, Maura, Meeteren, Schouten-van, Mueller, Sabine, Nicolaides, Theo, Perilongo, Giorgio, Tabori, Uri, Vezina, Gilbert, Warren, Katherine, Witt, Olaf, Zhu, Yuan, Jones, David T, and Kieran, Mark

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Pediatric, Neurosciences, Brain Cancer, Cancer, Brain Disorders, Good Health and Well Being, Brain Neoplasms, Child, Glioma, Humans, Molecular Targeted Therapy, Signal Transduction, low-grade glioma, neurofibromatosis type 1, pediatric brain tumor, pilocytic astrocytoma, RAS/MAPK pathway, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

For the past decade, it has been recognized that pediatric low-grade gliomas (LGGs) and glial-neuronal tumors carry distinct molecular alterations with resultant aberrant intracellular signaling in the Ras-mitogen-activated protein kinase pathway. The conclusions and recommendations of a consensus conference of how best to integrate the growing body of molecular genetic information into tumor classifications and, more importantly, for future treatment of pediatric LGGs are summarized here. There is uniform agreement that molecular characterization must be incorporated into classification and is increasingly critical for appropriate management. Molecular-targeted therapies should be integrated expeditiously, but also carefully into the management of these tumors and success measured not only by radiographic responses or stability, but also by functional outcomes. These trials need to be carried out with the caveat that the long-term impact of molecularly targeted therapy on the developing nervous system, especially with long duration treatment, is essentially unknown.

Published
2017

47. Intertumoral Heterogeneity within Medulloblastoma Subgroups

Author

Cavalli, Florence MG, Remke, Marc, Rampasek, Ladislav, Peacock, John, Shih, David JH, Luu, Betty, Garzia, Livia, Torchia, Jonathon, Nor, Carolina, Morrissy, A Sorana, Agnihotri, Sameer, Thompson, Yuan Yao, Kuzan-Fischer, Claudia M, Farooq, Hamza, Isaev, Keren, Daniels, Craig, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Lee, Ji Yeoun, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Vasiljevic, Alexandre, Faure-Conter, Cecile, Jouvet, Anne, Giannini, Caterina, Rao, Amulya A Nageswara, Li, Kay Ka Wai, Ng, Ho-Keung, Eberhart, Charles G, Pollack, Ian F, Hamilton, Ronald L, Gillespie, G Yancey, Olson, James M, Leary, Sarah, Weiss, William A, Lach, Boleslaw, Chambless, Lola B, Thompson, Reid C, Cooper, Michael K, Vibhakar, Rajeev, Hauser, Peter, van Veelen, Marie-Lise C, Kros, Johan M, French, Pim J, Ra, Young Shin, Kumabe, Toshihiro, López-Aguilar, Enrique, Zitterbart, Karel, Sterba, Jaroslav, Finocchiaro, Gaetano, Massimino, Maura, Van Meir, Erwin G, Osuka, Satoru, Shofuda, Tomoko, Klekner, Almos, Zollo, Massimo, Leonard, Jeffrey R, Rubin, Joshua B, Jabado, Nada, Albrecht, Steffen, Mora, Jaume, Van Meter, Timothy E, Jung, Shin, Moore, Andrew S, Hallahan, Andrew R, Chan, Jennifer A, Tirapelli, Daniela PC, Carlotti, Carlos G, Fouladi, Maryam, Pimentel, José, Faria, Claudia C, Saad, Ali G, Massimi, Luca, Liau, Linda M, Wheeler, Helen, Nakamura, Hideo, Elbabaa, Samer K, Perezpeña-Diazconti, Mario, de León, Fernando Chico Ponce, Robinson, Shenandoah, Zapotocky, Michal, Lassaletta, Alvaro, Huang, Annie, Hawkins, Cynthia E, Tabori, Uri, Bouffet, Eric, Bartels, Ute, Dirks, Peter B, Rutka, James T, Bader, Gary D, Reimand, Jüri, Goldenberg, Anna, Ramaswamy, Vijay, and Taylor, Michael D

Subjects
Genetics, Rare Diseases, Pediatric Cancer, Cancer, Brain Cancer, Pediatric Research Initiative, Pediatric, Human Genome, Brain Disorders, Cluster Analysis, Cohort Studies, DNA Copy Number Variations, DNA Methylation, Gene Expression Profiling, Genomics, Humans, Medulloblastoma, Precision Medicine, copy number, gene expression, integrative clustering, medulloblastoma, methylation, subgroups, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Published
2017

48. Pediatric high-grade glioma: biologically and clinically in need of new thinking.

Author

Jones, Chris, Karajannis, Matthias A, Jones, David TW, Kieran, Mark W, Monje, Michelle, Baker, Suzanne J, Becher, Oren J, Cho, Yoon-Jae, Gupta, Nalin, Hawkins, Cynthia, Hargrave, Darren, Haas-Kogan, Daphne A, Jabado, Nada, Li, Xiao-Nan, Mueller, Sabine, Nicolaides, Theo, Packer, Roger J, Persson, Anders I, Phillips, Joanna J, Simonds, Erin F, Stafford, James M, Tang, Yujie, Pfister, Stefan M, and Weiss, William A

Subjects
Humans, Glioma, Brain Neoplasms, Cell Transformation, Neoplastic, Prognosis, Child, Neoplasm Grading, DIPG, clinical trials, genomics, glioma, pediatric, Clinical Trials and Supportive Activities, Rare Diseases, Brain Cancer, Neurosciences, Brain Disorders, Pediatric, Cancer, Clinical Research, Orphan Drug, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.

Published
2017

49. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

Author

Kilburn, Lindsay B; https://orcid.org/0000-0003-1478-3619, Khuong-Quang, Dong-Anh; https://orcid.org/0000-0001-6305-7790, Hansford, Jordan R; https://orcid.org/0000-0001-7733-383X, Landi, Daniel, van der Lugt, Jasper; https://orcid.org/0000-0002-8186-338X, Leary, Sarah E S; https://orcid.org/0000-0003-0225-6184, Driever, Pablo Hernáiz; https://orcid.org/0000-0003-3135-3872, Bailey, Simon; https://orcid.org/0000-0003-4763-4329, Perreault, Sébastien, McCowage, Geoffrey, Waanders, Angela J, Ziegler, David S; https://orcid.org/0000-0001-7451-7916, Witt, Olaf, Baxter, Patricia A, Kang, Hyoung Jin; https://orcid.org/0000-0003-1009-6002, Hassall, Timothy E, Han, Jung Woo; https://orcid.org/0000-0001-8936-1205, Hargrave, Darren; https://orcid.org/0000-0001-8219-9807, Franson, Andrea T; https://orcid.org/0000-0002-5361-7683, Yalon Oren, Michal, Toledano, Helen, Larouche, Valérie; https://orcid.org/0000-0003-4082-7267, Kline, Cassie; https://orcid.org/0000-0001-7765-7690, Abdelbaki, Mohamed S, Jabado, Nada; https://orcid.org/0000-0003-2485-3692, Gottardo, Nicholas G; https://orcid.org/0000-0002-1082-6776, Gerber, Nicolas U; https://orcid.org/0000-0002-1783-631X, Whipple, Nicholas S, Segal, Devorah; https://orcid.org/0000-0002-9740-1286, Chi, Susan N, et al, Kilburn, Lindsay B; https://orcid.org/0000-0003-1478-3619, Khuong-Quang, Dong-Anh; https://orcid.org/0000-0001-6305-7790, Hansford, Jordan R; https://orcid.org/0000-0001-7733-383X, Landi, Daniel, van der Lugt, Jasper; https://orcid.org/0000-0002-8186-338X, Leary, Sarah E S; https://orcid.org/0000-0003-0225-6184, Driever, Pablo Hernáiz; https://orcid.org/0000-0003-3135-3872, Bailey, Simon; https://orcid.org/0000-0003-4763-4329, Perreault, Sébastien, McCowage, Geoffrey, Waanders, Angela J, Ziegler, David S; https://orcid.org/0000-0001-7451-7916, Witt, Olaf, Baxter, Patricia A, Kang, Hyoung Jin; https://orcid.org/0000-0003-1009-6002, Hassall, Timothy E, Han, Jung Woo; https://orcid.org/0000-0001-8936-1205, Hargrave, Darren; https://orcid.org/0000-0001-8219-9807, Franson, Andrea T; https://orcid.org/0000-0002-5361-7683, Yalon Oren, Michal, Toledano, Helen, Larouche, Valérie; https://orcid.org/0000-0003-4082-7267, Kline, Cassie; https://orcid.org/0000-0001-7765-7690, Abdelbaki, Mohamed S, Jabado, Nada; https://orcid.org/0000-0003-2485-3692, Gottardo, Nicholas G; https://orcid.org/0000-0002-1082-6776, Gerber, Nicolas U; https://orcid.org/0000-0002-1783-631X, Whipple, Nicholas S, Segal, Devorah; https://orcid.org/0000-0002-9740-1286, Chi, Susan N, and et al

Abstract

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m$^{-}$$^{2}$ once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .

Published
2024

50. Canadian Consensus for Treatment of BRAF V600E Mutated Pediatric and AYA Gliomas.

Author

Erker, Craig, Vanan, Magimairajan Issai, Larouche, Valérie, Nobre, Liana, Cacciotti, Chantel, Vairy, Stéphanie, Zelcer, Shayna, Fleming, Adam, Bouffet, Eric, Jabado, Nada, Legault, Geneviève, Renzi, Samuele, McKeown, Tara, Crooks, Bruce, Thacker, Nirav, Ramaswamy, Vijay, Coltin, Hallie, Lafay-Cousin, Lucie, Cheng, Sylvia, and Hukin, Juliette

Subjects
BRAF genes, GLIOMAS, TERMINATION of treatment, YOUNG adults, TREATMENT duration
Abstract

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm. [ABSTRACT FROM AUTHOR]

Published
2024
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