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10 results on '"Diana M. Carvalho"'

1. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation

Author

Prasidda Khadka, Zachary J. Reitman, Sophie Lu, Graham Buchan, Gabrielle Gionet, Frank Dubois, Diana M. Carvalho, Juliann Shih, Shu Zhang, Noah F. Greenwald, Travis Zack, Ofer Shapira, Kristine Pelton, Rachel Hartley, Heather Bear, Yohanna Georgis, Spandana Jarmale, Randy Melanson, Kevin Bonanno, Kathleen Schoolcraft, Peter G. Miller, Alexandra L. Condurat, Elizabeth M. Gonzalez, Kenin Qian, Eric Morin, Jaldeep Langhnoja, Leslie E. Lupien, Veronica Rendo, Jeromy Digiacomo, Dayle Wang, Kevin Zhou, Rushil Kumbhani, Maria E. Guerra Garcia, Claire E. Sinai, Sarah Becker, Rachel Schneider, Jayne Vogelzang, Karsten Krug, Amy Goodale, Tanaz Abid, Zohra Kalani, Federica Piccioni, Rameen Beroukhim, Nicole S. Persky, David E. Root, Angel M. Carcaboso, Benjamin L. Ebert, Christine Fuller, Ozgun Babur, Mark W. Kieran, Chris Jones, Hasmik Keshishian, Keith L. Ligon, Steven A. Carr, Timothy N. Phoenix, and Pratiti Bandopadhayay

Subjects
Science
Abstract

Abstract The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.

Published
2022
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2. PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma

Author

Nathan R. Fons, Ranjini K. Sundaram, Gregory A. Breuer, Sen Peng, Ryan L. McLean, Aravind N. Kalathil, Mark S. Schmidt, Diana M. Carvalho, Alan Mackay, Chris Jones, Ángel M. Carcaboso, Javad Nazarian, Michael E. Berens, Charles Brenner, and Ranjit S. Bindra

Subjects
Science
Abstract

Mutations in the Protein Phosphatase PPM1D are oncogenic in certain cancers including diffuse intrinsic pontine glioma (DIPG). Here, the authors show that PPM1D mutations in DIPG induce the silencing of the nicotinic acid phosphoribosyltransferase gene and display synthetic lethality with nicotinamide phosphoribosyltransferase inhibitors.

Published
2019
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3. Supplementary Data from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

Author

Chris Jones, Darren Hargrave, Michael Hubank, Simon P. Robinson, Maria Vinci, Jacques Grill, Fernando Carceller, Lynley V. Marshall, Bassel Zebian, Juliet C. Gray, Shaun Wilson, Jenny Adamski, Susan Picton, Lisa Howell, Richard G. Grundy, Thomas S. Jacques, Amy R. Fairchild, Matthew Clarke, Jyoti S. Choudhary, Georgia Roumelioti, Lu Yu, Patricia O'Hare, Sarita Depani, Mark Stubbs, Paula Z. Proszek, Maria Antonietta Ajmone-Cat, Rebecca F. Rogers, Yura Grabovska, Valeria Molinari, Molina Das, Elisabet Fernandez, Giulia Pericoli, Jessica K.R. Boult, Sara Temelso, Alan Mackay, Diana M. Carvalho, and Elisa Izquierdo

Abstract

Supplementary Data from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

Published
2023
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4. Data from DIPG Harbors Alterations Targetable by MEK Inhibitors, with Acquired Resistance Mechanisms Overcome by Combinatorial Inhibition

Author

Chris Jones, Darren Hargrave, Michael Hubank, Simon P. Robinson, Maria Vinci, Jacques Grill, Fernando Carceller, Lynley V. Marshall, Bassel Zebian, Juliet C. Gray, Shaun Wilson, Jenny Adamski, Susan Picton, Lisa Howell, Richard G. Grundy, Thomas S. Jacques, Amy R. Fairchild, Matthew Clarke, Jyoti S. Choudhary, Georgia Roumelioti, Lu Yu, Patricia O'Hare, Sarita Depani, Mark Stubbs, Paula Z. Proszek, Maria Antonietta Ajmone-Cat, Rebecca F. Rogers, Yura Grabovska, Valeria Molinari, Molina Das, Elisabet Fernandez, Giulia Pericoli, Jessica K.R. Boult, Sara Temelso, Alan Mackay, Diana M. Carvalho, and Elisa Izquierdo

Abstract

The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation.Significance:We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic.This article is highlighted in the In This Issue feature, p. 587

Published
2023
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5. Supplementary Table S1 from Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Author

Chris Jones, David T.W. Jones, Thomas S. Jacques, David W. Ellison, Sergey Popov, David Capper, Maria Vinci, Andrea Carai, Angela Mastronuzzi, Suzanne J. Baker, Felix Sahm, Stefan M. Pfister, Christof M. Kramm, Andreas von Deimling, Lynley V. Marshall, Fernando Carceller, Darren R. Hargrave, Kristian Aquilina, Matthias A. Karajannis, David S. Ziegler, Mark J. Cowley, Maria Tsoli, Stephen P. Lowis, Timothy E.G. Hassall, Andrew S. Moore, Simon Bailey, Francesca Diomedi-Camassei, Giovanna Stefania Colafati, Evelina Miele, Clare Mitchell, Tabitha Bloom, Olaf Witt, Marc Zuckermann, Dominik Sturm, Barbara C. Worst, Lotte Hiddingh, Andrey Korshunov, Pablo Hernáiz Driever, Felipe Andreiuolo, Torsten Pietsch, Simone Hettmer, Kornelius Kerl, Winand N.M. Dinjens, Martin Ebinger, Martin U. Schuhmann, Jens Schittenhelm, Michael Karremann, Michael Capra, Jane B. Cryan, Michael Farrell, Petter Brandal, Thale Kristin Olsen, David A. Solomon, Monika Ashok Davare, Lissa Baird, Matthew D. Wood, Barbara Faganel Kotnik, Mara Popović, Shani Caspi, Ho-Keung Ng, Roger Packer, Irene Slavc, Christine Haberler, Matthias Preusser, Tobey J. Macdonald, Paula Z. Proszek, Debbie Hughes, Marc K. Rosenblum, Stephen W. Gilheeney, Ira J. Dunkel, Martin Sill, Simon P. Robinson, Jessica K.R. Boult, Rachael Natrajan, Claire Cairns, Bassel Zebian, Christopher Chandler, Safa Al-Sarraj, Lawrence J. Doey, Andrew J. Martin, Leslie Bridges, Matija Snuderl, David E. Kram, Uwe Kordes, Ulrich Schüller, Jeffrey Knipstein, Stephen Crosier, Mellissa Maybury, Catherine Rowe, Kathreena M. Kurian, Michael Hubank, Ji Wen, Wilda Orisme, James D. Dalton, Kelly Haupfear, Mark Kristiansen, Jane Chalker, Aimee Avery, Amy R. Fairchild, Alex Virasami, Louise Howell, Anna Burford, Valeria Molinari, Diana M. Carvalho, Sara Temelso, Elisa Izquierdo, Iris Stoler, Tejus A. Bale, Scott Newman, Ruth G. Tatevossian, Jessica C. Pickles, Britta Ismer, Alan Mackay, and Matthew Clarke

Abstract

Supplementary Table S1

Published
2023
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6. Supplementary Data from Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Author

Chris Jones, David T.W. Jones, Thomas S. Jacques, David W. Ellison, Sergey Popov, David Capper, Maria Vinci, Andrea Carai, Angela Mastronuzzi, Suzanne J. Baker, Felix Sahm, Stefan M. Pfister, Christof M. Kramm, Andreas von Deimling, Lynley V. Marshall, Fernando Carceller, Darren R. Hargrave, Kristian Aquilina, Matthias A. Karajannis, David S. Ziegler, Mark J. Cowley, Maria Tsoli, Stephen P. Lowis, Timothy E.G. Hassall, Andrew S. Moore, Simon Bailey, Francesca Diomedi-Camassei, Giovanna Stefania Colafati, Evelina Miele, Clare Mitchell, Tabitha Bloom, Olaf Witt, Marc Zuckermann, Dominik Sturm, Barbara C. Worst, Lotte Hiddingh, Andrey Korshunov, Pablo Hernáiz Driever, Felipe Andreiuolo, Torsten Pietsch, Simone Hettmer, Kornelius Kerl, Winand N.M. Dinjens, Martin Ebinger, Martin U. Schuhmann, Jens Schittenhelm, Michael Karremann, Michael Capra, Jane B. Cryan, Michael Farrell, Petter Brandal, Thale Kristin Olsen, David A. Solomon, Monika Ashok Davare, Lissa Baird, Matthew D. Wood, Barbara Faganel Kotnik, Mara Popović, Shani Caspi, Ho-Keung Ng, Roger Packer, Irene Slavc, Christine Haberler, Matthias Preusser, Tobey J. Macdonald, Paula Z. Proszek, Debbie Hughes, Marc K. Rosenblum, Stephen W. Gilheeney, Ira J. Dunkel, Martin Sill, Simon P. Robinson, Jessica K.R. Boult, Rachael Natrajan, Claire Cairns, Bassel Zebian, Christopher Chandler, Safa Al-Sarraj, Lawrence J. Doey, Andrew J. Martin, Leslie Bridges, Matija Snuderl, David E. Kram, Uwe Kordes, Ulrich Schüller, Jeffrey Knipstein, Stephen Crosier, Mellissa Maybury, Catherine Rowe, Kathreena M. Kurian, Michael Hubank, Ji Wen, Wilda Orisme, James D. Dalton, Kelly Haupfear, Mark Kristiansen, Jane Chalker, Aimee Avery, Amy R. Fairchild, Alex Virasami, Louise Howell, Anna Burford, Valeria Molinari, Diana M. Carvalho, Sara Temelso, Elisa Izquierdo, Iris Stoler, Tejus A. Bale, Scott Newman, Ruth G. Tatevossian, Jessica C. Pickles, Britta Ismer, Alan Mackay, and Matthew Clarke

Abstract

Supplementary Figures and Legends

Published
2023
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7. Data from Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Author

Chris Jones, David T.W. Jones, Thomas S. Jacques, David W. Ellison, Sergey Popov, David Capper, Maria Vinci, Andrea Carai, Angela Mastronuzzi, Suzanne J. Baker, Felix Sahm, Stefan M. Pfister, Christof M. Kramm, Andreas von Deimling, Lynley V. Marshall, Fernando Carceller, Darren R. Hargrave, Kristian Aquilina, Matthias A. Karajannis, David S. Ziegler, Mark J. Cowley, Maria Tsoli, Stephen P. Lowis, Timothy E.G. Hassall, Andrew S. Moore, Simon Bailey, Francesca Diomedi-Camassei, Giovanna Stefania Colafati, Evelina Miele, Clare Mitchell, Tabitha Bloom, Olaf Witt, Marc Zuckermann, Dominik Sturm, Barbara C. Worst, Lotte Hiddingh, Andrey Korshunov, Pablo Hernáiz Driever, Felipe Andreiuolo, Torsten Pietsch, Simone Hettmer, Kornelius Kerl, Winand N.M. Dinjens, Martin Ebinger, Martin U. Schuhmann, Jens Schittenhelm, Michael Karremann, Michael Capra, Jane B. Cryan, Michael Farrell, Petter Brandal, Thale Kristin Olsen, David A. Solomon, Monika Ashok Davare, Lissa Baird, Matthew D. Wood, Barbara Faganel Kotnik, Mara Popović, Shani Caspi, Ho-Keung Ng, Roger Packer, Irene Slavc, Christine Haberler, Matthias Preusser, Tobey J. Macdonald, Paula Z. Proszek, Debbie Hughes, Marc K. Rosenblum, Stephen W. Gilheeney, Ira J. Dunkel, Martin Sill, Simon P. Robinson, Jessica K.R. Boult, Rachael Natrajan, Claire Cairns, Bassel Zebian, Christopher Chandler, Safa Al-Sarraj, Lawrence J. Doey, Andrew J. Martin, Leslie Bridges, Matija Snuderl, David E. Kram, Uwe Kordes, Ulrich Schüller, Jeffrey Knipstein, Stephen Crosier, Mellissa Maybury, Catherine Rowe, Kathreena M. Kurian, Michael Hubank, Ji Wen, Wilda Orisme, James D. Dalton, Kelly Haupfear, Mark Kristiansen, Jane Chalker, Aimee Avery, Amy R. Fairchild, Alex Virasami, Louise Howell, Anna Burford, Valeria Molinari, Diana M. Carvalho, Sara Temelso, Elisa Izquierdo, Iris Stoler, Tejus A. Bale, Scott Newman, Ruth G. Tatevossian, Jessica C. Pickles, Britta Ismer, Alan Mackay, and Matthew Clarke

Abstract

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Published
2023
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8. Data from Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1-Mutant Diffuse Intrinsic Pontine Glioma

Author

Chris Jones, Fernando Carceller, Angel M. Carcaboso, Sabine Mueller, Andres Morales La Madrid, Ofelia Cruz, Michael Hubank, Jacques Grill, Jeremy Pryce, Ashirwad Merve, Safa Al-Sarraj, Bassel Zebian, Andrew Mackinnon, David Sheppard, Anne Phelan, John P. Overington, Alan Mackay, Sara Temelso, Florence I. Raynaud, Akos Pal, Adam Donovan, Ruth Ruddle, Daniel P. Smith, Elizabeth A. Corley, Valeria Molinari, Cinzia Lavarino, Reda Stankunaite, Nagore Olaciregui, Peter J. Richardson, and Diana M. Carvalho

Abstract

Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence–based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood–brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies.Significance:Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.This article is highlighted in the In This Issue feature, p. 275

Published
2023
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9. Supplementary Figures S1-S3 from Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1-Mutant Diffuse Intrinsic Pontine Glioma

Author

Chris Jones, Fernando Carceller, Angel M. Carcaboso, Sabine Mueller, Andres Morales La Madrid, Ofelia Cruz, Michael Hubank, Jacques Grill, Jeremy Pryce, Ashirwad Merve, Safa Al-Sarraj, Bassel Zebian, Andrew Mackinnon, David Sheppard, Anne Phelan, John P. Overington, Alan Mackay, Sara Temelso, Florence I. Raynaud, Akos Pal, Adam Donovan, Ruth Ruddle, Daniel P. Smith, Elizabeth A. Corley, Valeria Molinari, Cinzia Lavarino, Reda Stankunaite, Nagore Olaciregui, Peter J. Richardson, and Diana M. Carvalho

Abstract

Supplementary Figures S1-S3

Published
2023
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10. DDEL-06. Drug Delivery to the Pons Using Short-Pulse Focused Ultrasound and Microbubble Exposure for the Treatment of Diffuse Midline Glioma

Author

Dani Chattenton, Ian Rivens, Zheng Jiang, Diana M Carvalho, Krit Sujarittam, Jessica K R Boult, Simon P Robinson, Chris Jones, Gail ter Haar, and James Choi

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

Despite advances in understanding diffuse midline glioma (DMG-H3K27), including DIPG, there are still no effective treatments available, and the dismal clinical prognosis remains. This is partly because of tumour spread behind an intact blood brain barrier (BBB), preventing drug delivery and the reason for many drugs failing in the clinic. The use of focused ultrasound and intravenous microbubbles enables temporary increases in BBB permeability, allowing drugs to enter the targeted brain region. Building on recent research demonstrating that short pulses (

Published
2022
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