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Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Previous studies have elucidated the genomic landscape of MB leading to the recognition of four core molecular subgroups (WNT, SHH, group 3 and group 4) with distinct clinical outcomes. Group 3 has the worst prognosis of all MB...

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Autores principales: Sengupta, Satarupa, Senthil Kumar, Shiva, Bondra, Kathryn, Sobo, Matthew, Mo, Xiaokui, Drissi, Rachid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891285/
https://www.ncbi.nlm.nih.gov/pubmed/36741010
http://dx.doi.org/10.3389/fonc.2023.1104670
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author Sengupta, Satarupa
Senthil Kumar, Shiva
Bondra, Kathryn
Sobo, Matthew
Mo, Xiaokui
Drissi, Rachid
author_facet Sengupta, Satarupa
Senthil Kumar, Shiva
Bondra, Kathryn
Sobo, Matthew
Mo, Xiaokui
Drissi, Rachid
author_sort Sengupta, Satarupa
collection PubMed
description Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Previous studies have elucidated the genomic landscape of MB leading to the recognition of four core molecular subgroups (WNT, SHH, group 3 and group 4) with distinct clinical outcomes. Group 3 has the worst prognosis of all MB. Radiotherapy (RT) remains a major component in the treatment of poor prognosis MB but is rarely curative alone and is associated with acute and long-term toxicities. A hallmark of cancer cells is their unlimited proliferative potential which correlates closely with telomere length. The vast majority of malignant tumors activate telomerase to maintain telomere length, whereas this activity is barely detectable in most normal human somatic tissues, making telomerase inhibition a rational therapeutic target in the setting of cancer recurrence and therapy resistance. We and others have previously shown that short telomeres confer sensitivity to ionizing radiation (IR) suggesting that telomerase inhibition mediated telomere shortening will improve the efficacy of RT while minimizing its side effects. Here, we investigated the efficacy of the combination of IR with IMT, a potent telomerase inhibitor, in an in vivo model of group 3 MB. Our results indicate that although IMT inhibited MB telomerase activity resulting in telomere shortening and delayed tumor growth, the combination with IR did not prevent tumor recurrence and did not improve survival compared to the treatment with IR alone. Together, these findings suggest that the radiosensitization by direct telomerase inhibition is not an effective approach to treat high-risk pediatric brain tumors.
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spelling pubmed-98912852023-02-02 Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma Sengupta, Satarupa Senthil Kumar, Shiva Bondra, Kathryn Sobo, Matthew Mo, Xiaokui Drissi, Rachid Front Oncol Oncology Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Previous studies have elucidated the genomic landscape of MB leading to the recognition of four core molecular subgroups (WNT, SHH, group 3 and group 4) with distinct clinical outcomes. Group 3 has the worst prognosis of all MB. Radiotherapy (RT) remains a major component in the treatment of poor prognosis MB but is rarely curative alone and is associated with acute and long-term toxicities. A hallmark of cancer cells is their unlimited proliferative potential which correlates closely with telomere length. The vast majority of malignant tumors activate telomerase to maintain telomere length, whereas this activity is barely detectable in most normal human somatic tissues, making telomerase inhibition a rational therapeutic target in the setting of cancer recurrence and therapy resistance. We and others have previously shown that short telomeres confer sensitivity to ionizing radiation (IR) suggesting that telomerase inhibition mediated telomere shortening will improve the efficacy of RT while minimizing its side effects. Here, we investigated the efficacy of the combination of IR with IMT, a potent telomerase inhibitor, in an in vivo model of group 3 MB. Our results indicate that although IMT inhibited MB telomerase activity resulting in telomere shortening and delayed tumor growth, the combination with IR did not prevent tumor recurrence and did not improve survival compared to the treatment with IR alone. Together, these findings suggest that the radiosensitization by direct telomerase inhibition is not an effective approach to treat high-risk pediatric brain tumors. Frontiers Media S.A. 2023-01-18 /pmc/articles/PMC9891285/ /pubmed/36741010 http://dx.doi.org/10.3389/fonc.2023.1104670 Text en Copyright © 2023 Sengupta, Senthil Kumar, Bondra, Sobo, Mo and Drissi https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Sengupta, Satarupa
Senthil Kumar, Shiva
Bondra, Kathryn
Sobo, Matthew
Mo, Xiaokui
Drissi, Rachid
Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma
title Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma
title_full Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma
title_fullStr Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma
title_full_unstemmed Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma
title_short Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma
title_sort limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891285/
https://www.ncbi.nlm.nih.gov/pubmed/36741010
http://dx.doi.org/10.3389/fonc.2023.1104670
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