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Article

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

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Clinic for Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Beijing Neurosurgical Institute, Tiantan Hospital, Beijing 100050, China
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Institute of Neuropathology, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Leibniz Research Institute for Environmental Medicine (IUF) and Medical Faculty Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
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Department of Clinical Neurosciences and WT-MRC Stem Cell Institute, University of Cambridge, Cambridge CB2 1QN, UK
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German Consortium for Translational Cancer Research (DKTK), Essen/Düsseldorf, 40225 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3859; https://doi.org/10.3390/cancers12123859
Received: 8 November 2020 / Revised: 15 December 2020 / Accepted: 18 December 2020 / Published: 21 December 2020
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
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.
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. View Full-Text
Keywords: glioblastoma; rapalink-1; tumor treating fields; EMT; therapy resistance; human stem cell in vitro platform; drug development; risk assessment; mTOR glioblastoma; rapalink-1; tumor treating fields; EMT; therapy resistance; human stem cell in vitro platform; drug development; risk assessment; mTOR
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MDPI and ACS Style

Vargas-Toscano, A.; Nickel, A.-C.; Li, G.; Kamp, M.A.; Muhammad, S.; Leprivier, G.; Fritsche, E.; Barker, R.A.; Sabel, M.; Steiger, H.-J.; Zhang, W.; Hänggi, D.; Kahlert, U.D. Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide. Cancers 2020, 12, 3859. https://doi.org/10.3390/cancers12123859

AMA Style

Vargas-Toscano A, Nickel A-C, Li G, Kamp MA, Muhammad S, Leprivier G, Fritsche E, Barker RA, Sabel M, Steiger H-J, Zhang W, Hänggi D, Kahlert UD. Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide. Cancers. 2020; 12(12):3859. https://doi.org/10.3390/cancers12123859

Chicago/Turabian Style

Vargas-Toscano, Andres, Ann-Christin Nickel, Guanzhang Li, Marcel A. Kamp, Sajjad Muhammad, Gabriel Leprivier, Ellen Fritsche, Roger A. Barker, Michael Sabel, Hans-Jakob Steiger, Wei Zhang, Daniel Hänggi, and Ulf D. Kahlert 2020. "Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide" Cancers 12, no. 12: 3859. https://doi.org/10.3390/cancers12123859

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