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Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide

SIMPLE SUMMARY: Glioblastoma (GBM) resistance to standard treatment is driven by stem-like cell behavior and epithelial-like-mesenchymal transition. The main purpose of this paper was to functionally validate a novel discovered pharmacological strategy to treat GBM, the dual mTOR pathway inhibitor R...

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Autores principales: Vargas-Toscano, Andres, Nickel, Ann-Christin, Li, Guanzhang, Kamp, Marcel Alexander, Muhammad, Sajjad, Leprivier, Gabriel, Fritsche, Ellen, Barker, Roger A., Sabel, Michael, Steiger, Hans-Jakob, Zhang, Wei, Hänggi, Daniel, Kahlert, Ulf Dietrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766508/
https://www.ncbi.nlm.nih.gov/pubmed/33371210
http://dx.doi.org/10.3390/cancers12123859
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author Vargas-Toscano, Andres
Nickel, Ann-Christin
Li, Guanzhang
Kamp, Marcel Alexander
Muhammad, Sajjad
Leprivier, Gabriel
Fritsche, Ellen
Barker, Roger A.
Sabel, Michael
Steiger, Hans-Jakob
Zhang, Wei
Hänggi, Daniel
Kahlert, Ulf Dietrich
author_facet Vargas-Toscano, Andres
Nickel, Ann-Christin
Li, Guanzhang
Kamp, Marcel Alexander
Muhammad, Sajjad
Leprivier, Gabriel
Fritsche, Ellen
Barker, Roger A.
Sabel, Michael
Steiger, Hans-Jakob
Zhang, Wei
Hänggi, Daniel
Kahlert, Ulf Dietrich
author_sort Vargas-Toscano, Andres
collection PubMed
description SIMPLE SUMMARY: Glioblastoma (GBM) resistance to standard treatment is driven by stem-like cell behavior and epithelial-like-mesenchymal transition. The main purpose of this paper was to functionally validate a novel discovered pharmacological strategy to treat GBM, the dual mTOR pathway inhibitor Rapalink-1 (RL1) using relevant stem cell models of the disease to unravel mechanistic insights. Our approach also interrogates combination studies with clinical treatment options of tumor treating fields (TTFields) and the best standard of care chemotherapy, temozolomide (TMZ). We provided clinical relevance of our experimental work through in silico evaluation on molecular data of diverse patient samples. RL1 effectively impaired motility and clonogenicity of GBM stem cells and reduced the expression of stem cell molecules. We elucidated a synergistic therapeutic potential of the inhibitor with TTFields to minimize therapy resistance toward TMZ, which supports its consideration for further translational oriented studies. ABSTRACT: Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of physiological relevant organoid-like stem cell models of GBM and studied the effect of RL1 exposure on various cellular features as well as on the expression of mTOR signaling targets and stem cell molecules. We also undertook combination treatments with this agent and clinical GBM treatments tumor treating fields (TTFields) and the standard-of-care drug temozolomide, TMZ. Low nanomolar (nM) RL1 treatment significantly reduced cell growth, proliferation, migration, and clonogenic potential of our stem cell models. It acted synergistically to reduce cell growth when applied in combination with TMZ and TTFields. We performed an in silico analysis from the molecular data of diverse patient samples to probe for a relationship between the expression of mTOR genes, and mesenchymal markers in different GBM cohorts. We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology.
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spelling pubmed-77665082020-12-28 Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide Vargas-Toscano, Andres Nickel, Ann-Christin Li, Guanzhang Kamp, Marcel Alexander Muhammad, Sajjad Leprivier, Gabriel Fritsche, Ellen Barker, Roger A. Sabel, Michael Steiger, Hans-Jakob Zhang, Wei Hänggi, Daniel Kahlert, Ulf Dietrich Cancers (Basel) Article SIMPLE SUMMARY: Glioblastoma (GBM) resistance to standard treatment is driven by stem-like cell behavior and epithelial-like-mesenchymal transition. The main purpose of this paper was to functionally validate a novel discovered pharmacological strategy to treat GBM, the dual mTOR pathway inhibitor Rapalink-1 (RL1) using relevant stem cell models of the disease to unravel mechanistic insights. Our approach also interrogates combination studies with clinical treatment options of tumor treating fields (TTFields) and the best standard of care chemotherapy, temozolomide (TMZ). We provided clinical relevance of our experimental work through in silico evaluation on molecular data of diverse patient samples. RL1 effectively impaired motility and clonogenicity of GBM stem cells and reduced the expression of stem cell molecules. We elucidated a synergistic therapeutic potential of the inhibitor with TTFields to minimize therapy resistance toward TMZ, which supports its consideration for further translational oriented studies. ABSTRACT: Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of physiological relevant organoid-like stem cell models of GBM and studied the effect of RL1 exposure on various cellular features as well as on the expression of mTOR signaling targets and stem cell molecules. We also undertook combination treatments with this agent and clinical GBM treatments tumor treating fields (TTFields) and the standard-of-care drug temozolomide, TMZ. Low nanomolar (nM) RL1 treatment significantly reduced cell growth, proliferation, migration, and clonogenic potential of our stem cell models. It acted synergistically to reduce cell growth when applied in combination with TMZ and TTFields. We performed an in silico analysis from the molecular data of diverse patient samples to probe for a relationship between the expression of mTOR genes, and mesenchymal markers in different GBM cohorts. We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology. MDPI 2020-12-21 /pmc/articles/PMC7766508/ /pubmed/33371210 http://dx.doi.org/10.3390/cancers12123859 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
Vargas-Toscano, Andres
Nickel, Ann-Christin
Li, Guanzhang
Kamp, Marcel Alexander
Muhammad, Sajjad
Leprivier, Gabriel
Fritsche, Ellen
Barker, Roger A.
Sabel, Michael
Steiger, Hans-Jakob
Zhang, Wei
Hänggi, Daniel
Kahlert, Ulf Dietrich
Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide
title Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide
title_full Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide
title_fullStr Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide
title_full_unstemmed Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide
title_short Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide
title_sort rapalink-1 targets glioblastoma stem cells and acts synergistically with tumor treating fields to reduce resistance against temozolomide
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766508/
https://www.ncbi.nlm.nih.gov/pubmed/33371210
http://dx.doi.org/10.3390/cancers12123859
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