Cargando…

High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas

Background: Meningiomas are the most common primary central nervous system tumors. 20–30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these...

Descripción completa

Detalles Bibliográficos
Autores principales: Tatman, Philip D., Wroblewski, Tadeusz H., Fringuello, Anthony R., Scherer, Samuel R., Foreman, William B., Damek, Denise M., Lillehei, Kevin, Youssef, A. Samy, Jensen, Randy L., Graner, Michael W., Ormond, D. Ryan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303324/
https://www.ncbi.nlm.nih.gov/pubmed/34300316
http://dx.doi.org/10.3390/jcm10143150
_version_ 1783727059485327360
author Tatman, Philip D.
Wroblewski, Tadeusz H.
Fringuello, Anthony R.
Scherer, Samuel R.
Foreman, William B.
Damek, Denise M.
Lillehei, Kevin
Youssef, A. Samy
Jensen, Randy L.
Graner, Michael W.
Ormond, D. Ryan
author_facet Tatman, Philip D.
Wroblewski, Tadeusz H.
Fringuello, Anthony R.
Scherer, Samuel R.
Foreman, William B.
Damek, Denise M.
Lillehei, Kevin
Youssef, A. Samy
Jensen, Randy L.
Graner, Michael W.
Ormond, D. Ryan
author_sort Tatman, Philip D.
collection PubMed
description Background: Meningiomas are the most common primary central nervous system tumors. 20–30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. Methods: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. Results: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. Conclusions: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use.
format Online
Article
Text
id pubmed-8303324
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83033242021-07-25 High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas Tatman, Philip D. Wroblewski, Tadeusz H. Fringuello, Anthony R. Scherer, Samuel R. Foreman, William B. Damek, Denise M. Lillehei, Kevin Youssef, A. Samy Jensen, Randy L. Graner, Michael W. Ormond, D. Ryan J Clin Med Article Background: Meningiomas are the most common primary central nervous system tumors. 20–30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors. Methods: In this study, we screened patient-cultured meningiomas with an epigenetic compound library to identify targetable mechanisms for the potential treatment of these tumors. Meningioma cell cultures were generated directly from surgically resected patient tumors and were cultured on a neural matrix. Cells were treated with a library of compounds meant to target epigenetic functions. Results: Although each tumor displayed a unique compound sensitivity profile, Panobinostat, LAQ824, and HC toxin were broadly effective across most tumors. These three compounds are broad-spectrum Histone Deacetylase (HDAC) inhibitors which target class I, IIa, and IIb HDACs. Panobinostat was identified as the most broadly effective compound, capable of significantly decreasing the average cell viability of the sample cohort, regardless of tumor grade, recurrence, radiation, and patient gender. Conclusions: These findings strongly suggest an important role of HDACs in meningioma biology and as a targetable mechanism. Additional validation studies are necessary to confirm these promising findings, as well to identify an ideal HDAC inhibitor candidate to develop for clinical use. MDPI 2021-07-16 /pmc/articles/PMC8303324/ /pubmed/34300316 http://dx.doi.org/10.3390/jcm10143150 Text en © 2021 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 Article
Tatman, Philip D.
Wroblewski, Tadeusz H.
Fringuello, Anthony R.
Scherer, Samuel R.
Foreman, William B.
Damek, Denise M.
Lillehei, Kevin
Youssef, A. Samy
Jensen, Randy L.
Graner, Michael W.
Ormond, D. Ryan
High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas
title High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas
title_full High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas
title_fullStr High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas
title_full_unstemmed High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas
title_short High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas
title_sort high-throughput mechanistic screening of epigenetic compounds for the potential treatment of meningiomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303324/
https://www.ncbi.nlm.nih.gov/pubmed/34300316
http://dx.doi.org/10.3390/jcm10143150
work_keys_str_mv AT tatmanphilipd highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT wroblewskitadeuszh highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT fringuelloanthonyr highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT scherersamuelr highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT foremanwilliamb highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT damekdenisem highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT lilleheikevin highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT youssefasamy highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT jensenrandyl highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT granermichaelw highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas
AT ormonddryan highthroughputmechanisticscreeningofepigeneticcompoundsforthepotentialtreatmentofmeningiomas