Cargando…
HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS
PDGFRA is commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a fatal disease with no current options for cure. We performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grad...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260101/ http://dx.doi.org/10.1093/neuonc/noad073.168 |
_version_ | 1785057788928458752 |
---|---|
author | Trissal, Maria Mayr, Lisa Schwark, Kallen LaBelle, Jenna Kong, Seongbae Furtner, Julia Weiler-Wichtl, Liesa Supko, Jeffrey Rozowsky, Jacob Hack, Olivia Groves, Andrew Marques, Joana Leiss, Ulrike Rosenmayr, Verena Dubois, Frank Greenwald, Noah F Madlener, Sibylle Guntner, Armin Sebastian Pálová, Hana Stepien, Natalia Lötsch-Gojo, Daniela Dorfer, Christian Dieckmann, Karen Peyrl, Andreas Azizi, Amadeo A Baumgartner, Alicia Slabý, Ondřej Pokorná, Petra Bandopadhayay, Pratiti Rameen_Beroukhim@dfci.harvard.edu Beroukhim, Rameen Beroukhim Ligon, Keith L Kramm, Christof M Bronsema, Annika Bailey, Simon Stucklin, Ana Guerreiro Mueller, Sabine Mueller Jones, David T W Jäger, Natalie Mullauer, Leonhard Haberler, Christine Kumar-Sinha, Chandan Chinnaiyan, Arul Mody, Rajen Sterba.Jaroslav@fnbrno.cz Štěrba, Jaroslav Štěrba Skrypek, Mary Martinez, Nina Bowers, Daniel C Koschmann, Carl Koschmann Gojo, Johannes Filbin, Mariella |
author_facet | Trissal, Maria Mayr, Lisa Schwark, Kallen LaBelle, Jenna Kong, Seongbae Furtner, Julia Weiler-Wichtl, Liesa Supko, Jeffrey Rozowsky, Jacob Hack, Olivia Groves, Andrew Marques, Joana Leiss, Ulrike Rosenmayr, Verena Dubois, Frank Greenwald, Noah F Madlener, Sibylle Guntner, Armin Sebastian Pálová, Hana Stepien, Natalia Lötsch-Gojo, Daniela Dorfer, Christian Dieckmann, Karen Peyrl, Andreas Azizi, Amadeo A Baumgartner, Alicia Slabý, Ondřej Pokorná, Petra Bandopadhayay, Pratiti Rameen_Beroukhim@dfci.harvard.edu Beroukhim, Rameen Beroukhim Ligon, Keith L Kramm, Christof M Bronsema, Annika Bailey, Simon Stucklin, Ana Guerreiro Mueller, Sabine Mueller Jones, David T W Jäger, Natalie Mullauer, Leonhard Haberler, Christine Kumar-Sinha, Chandan Chinnaiyan, Arul Mody, Rajen Sterba.Jaroslav@fnbrno.cz Štěrba, Jaroslav Štěrba Skrypek, Mary Martinez, Nina Bowers, Daniel C Koschmann, Carl Koschmann Gojo, Johannes Filbin, Mariella |
author_sort | Trissal, Maria |
collection | PubMed |
description | PDGFRA is commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a fatal disease with no current options for cure. We performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations in ~15% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors regardless of genomic alteration. Tumors with PDGFRA gene amplification demonstrated significantly elevated PDGFRA expression in both H3K27M DMGs and H3 wild-type pHGGs relative to tumors with wild-type or point mutated PDGFRA. We tested a range of PDGFRA inhibitors against a panel of patient derived pediatric H3K27M DMG, pHGG, and adult HGG. Amongst the inhibitors tested, avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA showed potent toxicity against a wide array of pediatric and adult cell lines. This molecule also demonstrated supra-micromolar blood brain barrier penetration in pre-clinical in vivo models, and demonstrated significant decrease in tumor growth and improved survival in orthotopic mouse xenograft models. Finally, building on this preclinical activity, we report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib usage showed no significant acute toxicities within this patient cohort. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced promising clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in pediatric high grade glioma. |
format | Online Article Text |
id | pubmed-10260101 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102601012023-06-13 HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS Trissal, Maria Mayr, Lisa Schwark, Kallen LaBelle, Jenna Kong, Seongbae Furtner, Julia Weiler-Wichtl, Liesa Supko, Jeffrey Rozowsky, Jacob Hack, Olivia Groves, Andrew Marques, Joana Leiss, Ulrike Rosenmayr, Verena Dubois, Frank Greenwald, Noah F Madlener, Sibylle Guntner, Armin Sebastian Pálová, Hana Stepien, Natalia Lötsch-Gojo, Daniela Dorfer, Christian Dieckmann, Karen Peyrl, Andreas Azizi, Amadeo A Baumgartner, Alicia Slabý, Ondřej Pokorná, Petra Bandopadhayay, Pratiti Rameen_Beroukhim@dfci.harvard.edu Beroukhim, Rameen Beroukhim Ligon, Keith L Kramm, Christof M Bronsema, Annika Bailey, Simon Stucklin, Ana Guerreiro Mueller, Sabine Mueller Jones, David T W Jäger, Natalie Mullauer, Leonhard Haberler, Christine Kumar-Sinha, Chandan Chinnaiyan, Arul Mody, Rajen Sterba.Jaroslav@fnbrno.cz Štěrba, Jaroslav Štěrba Skrypek, Mary Martinez, Nina Bowers, Daniel C Koschmann, Carl Koschmann Gojo, Johannes Filbin, Mariella Neuro Oncol Final Category: High Grade Glioma/Gliomatosis Cerebri - HGG PDGFRA is commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a fatal disease with no current options for cure. We performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations in ~15% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors regardless of genomic alteration. Tumors with PDGFRA gene amplification demonstrated significantly elevated PDGFRA expression in both H3K27M DMGs and H3 wild-type pHGGs relative to tumors with wild-type or point mutated PDGFRA. We tested a range of PDGFRA inhibitors against a panel of patient derived pediatric H3K27M DMG, pHGG, and adult HGG. Amongst the inhibitors tested, avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA showed potent toxicity against a wide array of pediatric and adult cell lines. This molecule also demonstrated supra-micromolar blood brain barrier penetration in pre-clinical in vivo models, and demonstrated significant decrease in tumor growth and improved survival in orthotopic mouse xenograft models. Finally, building on this preclinical activity, we report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib usage showed no significant acute toxicities within this patient cohort. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced promising clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in pediatric high grade glioma. Oxford University Press 2023-06-12 /pmc/articles/PMC10260101/ http://dx.doi.org/10.1093/neuonc/noad073.168 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Final Category: High Grade Glioma/Gliomatosis Cerebri - HGG Trissal, Maria Mayr, Lisa Schwark, Kallen LaBelle, Jenna Kong, Seongbae Furtner, Julia Weiler-Wichtl, Liesa Supko, Jeffrey Rozowsky, Jacob Hack, Olivia Groves, Andrew Marques, Joana Leiss, Ulrike Rosenmayr, Verena Dubois, Frank Greenwald, Noah F Madlener, Sibylle Guntner, Armin Sebastian Pálová, Hana Stepien, Natalia Lötsch-Gojo, Daniela Dorfer, Christian Dieckmann, Karen Peyrl, Andreas Azizi, Amadeo A Baumgartner, Alicia Slabý, Ondřej Pokorná, Petra Bandopadhayay, Pratiti Rameen_Beroukhim@dfci.harvard.edu Beroukhim, Rameen Beroukhim Ligon, Keith L Kramm, Christof M Bronsema, Annika Bailey, Simon Stucklin, Ana Guerreiro Mueller, Sabine Mueller Jones, David T W Jäger, Natalie Mullauer, Leonhard Haberler, Christine Kumar-Sinha, Chandan Chinnaiyan, Arul Mody, Rajen Sterba.Jaroslav@fnbrno.cz Štěrba, Jaroslav Štěrba Skrypek, Mary Martinez, Nina Bowers, Daniel C Koschmann, Carl Koschmann Gojo, Johannes Filbin, Mariella HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS |
title | HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS |
title_full | HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS |
title_fullStr | HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS |
title_full_unstemmed | HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS |
title_short | HGG-19. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS WITH H3K27M OR PDGFRA GENOMIC ALTERATIONS |
title_sort | hgg-19. clinical response to the pdgfra/kit inhibitor avapritinib in pediatric and young adult high-grade glioma patients with h3k27m or pdgfra genomic alterations |
topic | Final Category: High Grade Glioma/Gliomatosis Cerebri - HGG |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260101/ http://dx.doi.org/10.1093/neuonc/noad073.168 |
work_keys_str_mv | AT trissalmaria hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT mayrlisa hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT schwarkkallen hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT labellejenna hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT kongseongbae hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT furtnerjulia hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT weilerwichtlliesa hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT supkojeffrey hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT rozowskyjacob hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT hackolivia hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT grovesandrew hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT marquesjoana hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT leissulrike hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT rosenmayrverena hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT duboisfrank hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT greenwaldnoahf hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT madlenersibylle hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT guntnerarminsebastian hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT palovahana hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT stepiennatalia hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT lotschgojodaniela hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT dorferchristian hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT dieckmannkaren hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT peyrlandreas hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT aziziamadeoa hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT baumgartneralicia hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT slabyondrej hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT pokornapetra hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT bandopadhayaypratiti hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT rameenberoukhimdfciharvardeduberoukhimrameenberoukhim hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT ligonkeithl hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT krammchristofm hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT bronsemaannika hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT baileysimon hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT stucklinanaguerreiro hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT muellersabinemueller hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT jonesdavidtw hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT jagernatalie hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT mullauerleonhard hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT haberlerchristine hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT kumarsinhachandan hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT chinnaiyanarul hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT modyrajen hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT sterbajaroslavfnbrnoczsterbajaroslavsterba hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT skrypekmary hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT martineznina hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT bowersdanielc hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT koschmanncarlkoschmann hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT gojojohannes hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations AT filbinmariella hgg19clinicalresponsetothepdgfrakitinhibitoravapritinibinpediatricandyoungadulthighgradegliomapatientswithh3k27morpdgfragenomicalterations |