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Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. E...

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Detalles Bibliográficos
Autores principales: Peer, Elisabeth, Tesanovic, Suzana, Aberger, Fritz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520835/
https://www.ncbi.nlm.nih.gov/pubmed/30991683
http://dx.doi.org/10.3390/cancers11040538
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author Peer, Elisabeth
Tesanovic, Suzana
Aberger, Fritz
author_facet Peer, Elisabeth
Tesanovic, Suzana
Aberger, Fritz
author_sort Peer, Elisabeth
collection PubMed
description The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling.
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spelling pubmed-65208352019-05-31 Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy Peer, Elisabeth Tesanovic, Suzana Aberger, Fritz Cancers (Basel) Review The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling. MDPI 2019-04-15 /pmc/articles/PMC6520835/ /pubmed/30991683 http://dx.doi.org/10.3390/cancers11040538 Text en © 2019 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 Review
Peer, Elisabeth
Tesanovic, Suzana
Aberger, Fritz
Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
title Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
title_full Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
title_fullStr Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
title_full_unstemmed Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
title_short Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy
title_sort next-generation hedgehog/gli pathway inhibitors for cancer therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520835/
https://www.ncbi.nlm.nih.gov/pubmed/30991683
http://dx.doi.org/10.3390/cancers11040538
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