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Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma
Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clin...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766483/ https://www.ncbi.nlm.nih.gov/pubmed/33353026 http://dx.doi.org/10.3390/jpm10040290 |
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author | Mayr, Lisa Guntner, Armin S. Madlener, Sibylle Schmook, Maria T. Peyrl, Andreas Azizi, Amedeo A. Dieckmann, Karin Reisinger, Dominik Stepien, Natalia M. Schramm, Kathrin Laemmerer, Anna Jones, David T. W. Ecker, Jonas Sahm, Felix Milde, Till Pajtler, Kristian W. Blattner-Johnson, Mirjam Strbac, Miroslav Dorfer, Christian Czech, Thomas Kirchhofer, Dominik Gabler, Lisa Berger, Walter Haberler, Christine Müllauer, Leonhard Buchberger, Wolfgang Slavc, Irene Lötsch-Gojo, Daniela Gojo, Johannes |
author_facet | Mayr, Lisa Guntner, Armin S. Madlener, Sibylle Schmook, Maria T. Peyrl, Andreas Azizi, Amedeo A. Dieckmann, Karin Reisinger, Dominik Stepien, Natalia M. Schramm, Kathrin Laemmerer, Anna Jones, David T. W. Ecker, Jonas Sahm, Felix Milde, Till Pajtler, Kristian W. Blattner-Johnson, Mirjam Strbac, Miroslav Dorfer, Christian Czech, Thomas Kirchhofer, Dominik Gabler, Lisa Berger, Walter Haberler, Christine Müllauer, Leonhard Buchberger, Wolfgang Slavc, Irene Lötsch-Gojo, Daniela Gojo, Johannes |
author_sort | Mayr, Lisa |
collection | PubMed |
description | Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies. |
format | Online Article Text |
id | pubmed-7766483 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77664832020-12-28 Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma Mayr, Lisa Guntner, Armin S. Madlener, Sibylle Schmook, Maria T. Peyrl, Andreas Azizi, Amedeo A. Dieckmann, Karin Reisinger, Dominik Stepien, Natalia M. Schramm, Kathrin Laemmerer, Anna Jones, David T. W. Ecker, Jonas Sahm, Felix Milde, Till Pajtler, Kristian W. Blattner-Johnson, Mirjam Strbac, Miroslav Dorfer, Christian Czech, Thomas Kirchhofer, Dominik Gabler, Lisa Berger, Walter Haberler, Christine Müllauer, Leonhard Buchberger, Wolfgang Slavc, Irene Lötsch-Gojo, Daniela Gojo, Johannes J Pers Med Article Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies. MDPI 2020-12-18 /pmc/articles/PMC7766483/ /pubmed/33353026 http://dx.doi.org/10.3390/jpm10040290 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mayr, Lisa Guntner, Armin S. Madlener, Sibylle Schmook, Maria T. Peyrl, Andreas Azizi, Amedeo A. Dieckmann, Karin Reisinger, Dominik Stepien, Natalia M. Schramm, Kathrin Laemmerer, Anna Jones, David T. W. Ecker, Jonas Sahm, Felix Milde, Till Pajtler, Kristian W. Blattner-Johnson, Mirjam Strbac, Miroslav Dorfer, Christian Czech, Thomas Kirchhofer, Dominik Gabler, Lisa Berger, Walter Haberler, Christine Müllauer, Leonhard Buchberger, Wolfgang Slavc, Irene Lötsch-Gojo, Daniela Gojo, Johannes Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma |
title | Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma |
title_full | Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma |
title_fullStr | Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma |
title_full_unstemmed | Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma |
title_short | Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma |
title_sort | cerebrospinal fluid penetration and combination therapy of entrectinib for disseminated ros1/ntrk-fusion positive pediatric high-grade glioma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766483/ https://www.ncbi.nlm.nih.gov/pubmed/33353026 http://dx.doi.org/10.3390/jpm10040290 |
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