Effective targeting of PDGFRA-altered high-grade glioma with avapritinib
Autoři
MAYR, Lisa; Sina NEYAZI; Kallen SCHWARK; Maria TRISSAL; Alexander BECK; Jenna LABELLE; Sebastian K. EDER; Liesa WEILER-WICHTL; Joana G. MARQUES; Carlos A. O. Jr. DE BIAGI; Constanza LO CASCIO; Owen CHAPMAN; Sunita SRIDHAR; Rishaan KENKRE; Aditi DUTTA; Shanqing WANG; Jessica WANG; Olivia HACK; Andrezza NASCIMENTO; Cuong M. NGUYEN; Sophia CASTELLANI; Jacob S. ROZOWSKY; Andrew GROVES; Eshini PANDITHARATNA; Gustavo Alencastro Veiga CRUZEIRO; Rebecca D. HAASE; Kuscha TABATABAI; Sibylle MADLENER; Jack WADDEN; Tiffany ADAM; Seongbae KONG; Madeline MICLEA; Tirth PATEL; Katharina BRUCKNER; Daniel SENFTER; Anna LAEMMERER; Jeffrey SUPKO; Armin S GUNTNER; Hana PÁLOVÁ; Jakub NERADIL; Natalia STEPIEN; Daniela LOETSCH-GOJO; Walter BERGER; Ulrike LEISS; Verena ROSENMAYR; Christian DORFER; Karin DIECKMANN; Andreas PEYRL; Amedeo A. AZIZI; Alicia BAUMGARTNER; Ondřej SLABÝ; Petra POKORNÁ ORCID; Louise M. CLARK; Quang-De NGUYEN; Hiroaki WAKIMOTO; Frank DUBOIS; Noah F. GREENWALD; Pratiti BANDOPADHAYAY; Rameen BEROUKHIM; Amy CAMERON; Keith LIGON; Christof KRAMM; Annika BRONSEMA; Simon BAILEY; Ana Guerreiro STUCKLIN; Sabine MUELLER; Mary SKRYPEK; Nina MARTINEZ; Daniel C. BOWERS; David T. W. JONES; Chris JONES; Natalie JAEGER; Jaroslav ŠTĚRBA; Leonhard MUELLAUER; Christine HABERLER; Chandan KUMAR-SINHA; Arul CHINNAIYAN; Rajen MODY; Lukas CHAVEZ; Julia FURTNER; Carl KOSCHMANN; Johannes GOJO a Mariella G. FILBIN
Vydání
Cancer Cell, Cambridge, Cell Press, 2025, 1535-6108
PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.
Návaznosti
NU20-03-00240, projekt VaV
Název: Celoexomové sekvenování, sekvenování genomu s nízkým pokrytím a transkriptomu pro účely precizní onkologie u dětských pacientů s vysoce rizikovými a relabovanými solidními nádory
Investor: Ministerstvo zdravotnictví ČR, Celoexomové sekvenování, sekvenování genomu s nízkým pokrytím a transkriptomu pro účely precizní onkologie u dětských pacientů s vysoce rizikovými a relabovanými solidními nádory, Podprogram 1 - standardní
MAYR, Lisa; Sina NEYAZI; Kallen SCHWARK; Maria TRISSAL; Alexander BECK; Jenna LABELLE; Sebastian K. EDER; Liesa WEILER-WICHTL; Joana G. MARQUES; Carlos A. O. Jr. DE BIAGI; Constanza LO CASCIO; Owen CHAPMAN; Sunita SRIDHAR; Rishaan KENKRE; Aditi DUTTA; Shanqing WANG; Jessica WANG; Olivia HACK; Andrezza NASCIMENTO; Cuong M. NGUYEN; Sophia CASTELLANI; Jacob S. ROZOWSKY; Andrew GROVES; Eshini PANDITHARATNA; Gustavo Alencastro Veiga CRUZEIRO; Rebecca D. HAASE; Kuscha TABATABAI; Sibylle MADLENER; Jack WADDEN; Tiffany ADAM; Seongbae KONG; Madeline MICLEA; Tirth PATEL; Katharina BRUCKNER; Daniel SENFTER; Anna LAEMMERER; Jeffrey SUPKO; Armin S GUNTNER; Hana PÁLOVÁ; Jakub NERADIL; Natalia STEPIEN; Daniela LOETSCH-GOJO; Walter BERGER; Ulrike LEISS; Verena ROSENMAYR; Christian DORFER; Karin DIECKMANN; Andreas PEYRL; Amedeo A. AZIZI; Alicia BAUMGARTNER; Ondřej SLABÝ; Petra POKORNÁ; Louise M. CLARK; Quang-De NGUYEN; Hiroaki WAKIMOTO; Frank DUBOIS; Noah F. GREENWALD; Pratiti BANDOPADHAYAY; Rameen BEROUKHIM; Amy CAMERON; Keith LIGON; Christof KRAMM; Annika BRONSEMA; Simon BAILEY; Ana Guerreiro STUCKLIN; Sabine MUELLER; Mary SKRYPEK; Nina MARTINEZ; Daniel C. BOWERS; David T. W. JONES; Chris JONES; Natalie JAEGER; Jaroslav ŠTĚRBA; Leonhard MUELLAUER; Christine HABERLER; Chandan KUMAR-SINHA; Arul CHINNAIYAN; Rajen MODY; Lukas CHAVEZ; Julia FURTNER; Carl KOSCHMANN; Johannes GOJO a Mariella G. FILBIN. Effective targeting of PDGFRA-altered high-grade glioma with avapritinib. Cancer Cell. Cambridge: Cell Press, 2025, roč. 43, č. 4, s. 1-26. ISSN 1535-6108. Dostupné z: https://doi.org/10.1016/j.ccell.2025.02.018.
@article{2501029, author = {Mayr, Lisa and Neyazi, Sina and Schwark, Kallen and Trissal, Maria and Beck, Alexander and Labelle, Jenna and Eder, Sebastian K. and WeilerandWichtl, Liesa and Marques, Joana G. and de Biagi, Carlos A. O. Jr. and Lo Cascio, Constanza and Chapman, Owen and Sridhar, Sunita and Kenkre, Rishaan and Dutta, Aditi and Wang, Shanqing and Wang, Jessica and Hack, Olivia and Nascimento, Andrezza and Nguyen, Cuong M. and Castellani, Sophia and Rozowsky, Jacob S. and Groves, Andrew and Panditharatna, Eshini and Cruzeiro, Gustavo Alencastro Veiga and Haase, Rebecca D. and Tabatabai, Kuscha and Madlener, Sibylle and Wadden, Jack and Adam, Tiffany and Kong, Seongbae and Miclea, Madeline and Patel, Tirth and Bruckner, Katharina and Senfter, Daniel and Laemmerer, Anna and Supko, Jeffrey and Guntner, Armin S and Pálová, Hana and Neradil, Jakub and Stepien, Natalia and LoetschandGojo, Daniela and Berger, Walter and Leiss, Ulrike and Rosenmayr, Verena and Dorfer, Christian and Dieckmann, Karin and Peyrl, Andreas and Azizi, Amedeo A. and Baumgartner, Alicia and Slabý, Ondřej and Pokorná, Petra and Clark, Louise M. and Nguyen, QuangandDe and Wakimoto, Hiroaki and Dubois, Frank and Greenwald, Noah F. and Bandopadhayay, Pratiti and Beroukhim, Rameen and Cameron, Amy and Ligon, Keith and Kramm, Christof and Bronsema, Annika and Bailey, Simon and Stucklin, Ana Guerreiro and Mueller, Sabine and Skrypek, Mary and Martinez, Nina and Bowers, Daniel C. and Jones, David T. W. and Jones, Chris and Jaeger, Natalie and Štěrba, Jaroslav and Muellauer, Leonhard and Haberler, Christine and KumarandSinha, Chandan and Chinnaiyan, Arul and Mody, Rajen and Chavez, Lukas and Furtner, Julia and Koschmann, Carl and Gojo, Johannes and Filbin, Mariella G.}, article_location = {Cambridge}, article_number = {4}, doi = {https://doi.org/10.1016/j.ccell.2025.02.018}, keywords = {avapritinib; PDGFRA inhibitor; high-grade glioma; PDGFRA amplification; PDGFRA mutation; PDGFRA alteration; brain penetrance; diffuse midline glioma; glioblastoma; tyrosine kinase inhibitor}, language = {eng}, issn = {1535-6108}, journal = {Cancer Cell}, title = {Effective targeting of PDGFRA-altered high-grade glioma with avapritinib}, url = {https://www.sciencedirect.com/science/article/pii/S1535610825000704?via%3Dihub}, volume = {43}, year = {2025} }
TY - JOUR ID - 2501029 AU - Mayr, Lisa - Neyazi, Sina - Schwark, Kallen - Trissal, Maria - Beck, Alexander - Labelle, Jenna - Eder, Sebastian K. - Weiler-Wichtl, Liesa - Marques, Joana G. - de Biagi, Carlos A. O. Jr. - Lo Cascio, Constanza - Chapman, Owen - Sridhar, Sunita - Kenkre, Rishaan - Dutta, Aditi - Wang, Shanqing - Wang, Jessica - Hack, Olivia - Nascimento, Andrezza - Nguyen, Cuong M. - Castellani, Sophia - Rozowsky, Jacob S. - Groves, Andrew - Panditharatna, Eshini - Cruzeiro, Gustavo Alencastro Veiga - Haase, Rebecca D. - Tabatabai, Kuscha - Madlener, Sibylle - Wadden, Jack - Adam, Tiffany - Kong, Seongbae - Miclea, Madeline - Patel, Tirth - Bruckner, Katharina - Senfter, Daniel - Laemmerer, Anna - Supko, Jeffrey - Guntner, Armin S - Pálová, Hana - Neradil, Jakub - Stepien, Natalia - Loetsch-Gojo, Daniela - Berger, Walter - Leiss, Ulrike - Rosenmayr, Verena - Dorfer, Christian - Dieckmann, Karin - Peyrl, Andreas - Azizi, Amedeo A. - Baumgartner, Alicia - Slabý, Ondřej - Pokorná, Petra - Clark, Louise M. - Nguyen, Quang-De - Wakimoto, Hiroaki - Dubois, Frank - Greenwald, Noah F. - Bandopadhayay, Pratiti - Beroukhim, Rameen - Cameron, Amy - Ligon, Keith - Kramm, Christof - Bronsema, Annika - Bailey, Simon - Stucklin, Ana Guerreiro - Mueller, Sabine - Skrypek, Mary - Martinez, Nina - Bowers, Daniel C. - Jones, David T. W. - Jones, Chris - Jaeger, Natalie - Štěrba, Jaroslav - Muellauer, Leonhard - Haberler, Christine - Kumar-Sinha, Chandan - Chinnaiyan, Arul - Mody, Rajen - Chavez, Lukas - Furtner, Julia - Koschmann, Carl - Gojo, Johannes - Filbin, Mariella G. PY - 2025 TI - Effective targeting of PDGFRA-altered high-grade glioma with avapritinib JF - Cancer Cell VL - 43 IS - 4 SP - 1-26 EP - 1-26 PB - Cell Press SN - 15356108 KW - avapritinib KW - PDGFRA inhibitor KW - high-grade glioma KW - PDGFRA amplification KW - PDGFRA mutation KW - PDGFRA alteration KW - brain penetrance KW - diffuse midline glioma KW - glioblastoma KW - tyrosine kinase inhibitor UR - https://www.sciencedirect.com/science/article/pii/S1535610825000704?via%3Dihub N2 - PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG. ER -
MAYR, Lisa; Sina NEYAZI; Kallen SCHWARK; Maria TRISSAL; Alexander BECK; Jenna LABELLE; Sebastian K. EDER; Liesa WEILER-WICHTL; Joana G. MARQUES; Carlos A. O. Jr. DE BIAGI; Constanza LO CASCIO; Owen CHAPMAN; Sunita SRIDHAR; Rishaan KENKRE; Aditi DUTTA; Shanqing WANG; Jessica WANG; Olivia HACK; Andrezza NASCIMENTO; Cuong M. NGUYEN; Sophia CASTELLANI; Jacob S. ROZOWSKY; Andrew GROVES; Eshini PANDITHARATNA; Gustavo Alencastro Veiga CRUZEIRO; Rebecca D. HAASE; Kuscha TABATABAI; Sibylle MADLENER; Jack WADDEN; Tiffany ADAM; Seongbae KONG; Madeline MICLEA; Tirth PATEL; Katharina BRUCKNER; Daniel SENFTER; Anna LAEMMERER; Jeffrey SUPKO; Armin S GUNTNER; Hana PÁLOVÁ; Jakub NERADIL; Natalia STEPIEN; Daniela LOETSCH-GOJO; Walter BERGER; Ulrike LEISS; Verena ROSENMAYR; Christian DORFER; Karin DIECKMANN; Andreas PEYRL; Amedeo A. AZIZI; Alicia BAUMGARTNER; Ondřej SLABÝ; Petra POKORNÁ; Louise M. CLARK; Quang-De NGUYEN; Hiroaki WAKIMOTO; Frank DUBOIS; Noah F. GREENWALD; Pratiti BANDOPADHAYAY; Rameen BEROUKHIM; Amy CAMERON; Keith LIGON; Christof KRAMM; Annika BRONSEMA; Simon BAILEY; Ana Guerreiro STUCKLIN; Sabine MUELLER; Mary SKRYPEK; Nina MARTINEZ; Daniel C. BOWERS; David T. W. JONES; Chris JONES; Natalie JAEGER; Jaroslav ŠTĚRBA; Leonhard MUELLAUER; Christine HABERLER; Chandan KUMAR-SINHA; Arul CHINNAIYAN; Rajen MODY; Lukas CHAVEZ; Julia FURTNER; Carl KOSCHMANN; Johannes GOJO a Mariella G. FILBIN. Effective targeting of PDGFRA-altered high-grade glioma with avapritinib. \textit{Cancer Cell}. Cambridge: Cell Press, 2025, roč.~43, č.~4, s.~1-26. ISSN~1535-6108. Dostupné z: https://doi.org/10.1016/j.ccell.2025.02.018.