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Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma
SIMPLE SUMMARY: NB is a heterogenous childhood cancer from spontaneous regression to high-risk advanced malignancy. When the tumor is localized, it is generally treatable. However, the long-term survival rate for advanced metastatic NB is poor. Therefore, it is important to further investigate the s...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10452524/ https://www.ncbi.nlm.nih.gov/pubmed/37627018 http://dx.doi.org/10.3390/biology12081134 |
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author | Lan, Michael S. Chen, Chiachen |
author_facet | Lan, Michael S. Chen, Chiachen |
author_sort | Lan, Michael S. |
collection | PubMed |
description | SIMPLE SUMMARY: NB is a heterogenous childhood cancer from spontaneous regression to high-risk advanced malignancy. When the tumor is localized, it is generally treatable. However, the long-term survival rate for advanced metastatic NB is poor. Therefore, it is important to further investigate the specific target critical for suppression of NB tumor cell growth as a new treatment protocol that could lead to NB therapy. This review article discusses a recent approach of targeting a new NB biomarker, INSM1 and identifies several potential small molecules that inhibit INSM1 expression and its associated signaling pathway axis in NB. The newly identified small molecules represent either novel or FDA-approved repurposing compounds that could be beneficial for the treatment of high-risk NB. ABSTRACT: Human neuroblastoma (NB) is the most common childhood extracranial tumor arising from the sympathetic nervous system. It is also a clinically heterogeneous disease that ranges from spontaneous regression to high-risk stage 4 disease. The cause of this disease remains elusive. However, the amplification of NMYC oncogene occurred in roughly 30% of NB patients, which strongly correlated with the advanced stage of disease subtype and the worse prognosis status. We discovered that N-Myc oncoprotein binds and activates INSM1, a zinc-finger transcription factor of neuroendocrine tumors. We also found that INSM1 modulates N-Myc stability mediated through PI3K/AKT/GSK3β signaling pathway. Therefore, INSM1 emerges as a critical co-player with N-Myc in facilitating NB tumor cell growth and sustaining the advanced stage of malignancy. Using an INSM1-promoter driven luciferase screening-platform, we have recently identified fifteen small molecules that negatively regulate INSM1 expression. Interestingly, the identified small molecules can be divided into four large groups of compounds such as cell signaling inhibitor, DNA/RNA inhibitor, HDAC inhibitor, and cardiac glycoside. These findings support the presence of a unique mechanism associated with INSM1 and N-Myc interplay, which is critical in regulating NB tumor cell growth. We discuss the feasibility of identifying novel or repurposing small molecules targeting INSM1 as a potential treatment option for high-risk NB. |
format | Online Article Text |
id | pubmed-10452524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104525242023-08-26 Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma Lan, Michael S. Chen, Chiachen Biology (Basel) Review SIMPLE SUMMARY: NB is a heterogenous childhood cancer from spontaneous regression to high-risk advanced malignancy. When the tumor is localized, it is generally treatable. However, the long-term survival rate for advanced metastatic NB is poor. Therefore, it is important to further investigate the specific target critical for suppression of NB tumor cell growth as a new treatment protocol that could lead to NB therapy. This review article discusses a recent approach of targeting a new NB biomarker, INSM1 and identifies several potential small molecules that inhibit INSM1 expression and its associated signaling pathway axis in NB. The newly identified small molecules represent either novel or FDA-approved repurposing compounds that could be beneficial for the treatment of high-risk NB. ABSTRACT: Human neuroblastoma (NB) is the most common childhood extracranial tumor arising from the sympathetic nervous system. It is also a clinically heterogeneous disease that ranges from spontaneous regression to high-risk stage 4 disease. The cause of this disease remains elusive. However, the amplification of NMYC oncogene occurred in roughly 30% of NB patients, which strongly correlated with the advanced stage of disease subtype and the worse prognosis status. We discovered that N-Myc oncoprotein binds and activates INSM1, a zinc-finger transcription factor of neuroendocrine tumors. We also found that INSM1 modulates N-Myc stability mediated through PI3K/AKT/GSK3β signaling pathway. Therefore, INSM1 emerges as a critical co-player with N-Myc in facilitating NB tumor cell growth and sustaining the advanced stage of malignancy. Using an INSM1-promoter driven luciferase screening-platform, we have recently identified fifteen small molecules that negatively regulate INSM1 expression. Interestingly, the identified small molecules can be divided into four large groups of compounds such as cell signaling inhibitor, DNA/RNA inhibitor, HDAC inhibitor, and cardiac glycoside. These findings support the presence of a unique mechanism associated with INSM1 and N-Myc interplay, which is critical in regulating NB tumor cell growth. We discuss the feasibility of identifying novel or repurposing small molecules targeting INSM1 as a potential treatment option for high-risk NB. MDPI 2023-08-15 /pmc/articles/PMC10452524/ /pubmed/37627018 http://dx.doi.org/10.3390/biology12081134 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Lan, Michael S. Chen, Chiachen Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma |
title | Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma |
title_full | Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma |
title_fullStr | Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma |
title_full_unstemmed | Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma |
title_short | Small Molecules Targeting INSM1 for the Treatment of High-Risk Neuroblastoma |
title_sort | small molecules targeting insm1 for the treatment of high-risk neuroblastoma |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10452524/ https://www.ncbi.nlm.nih.gov/pubmed/37627018 http://dx.doi.org/10.3390/biology12081134 |
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