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      Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer

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          Abstract

          The Hedgehog/GLI signaling pathway plays an important role in normal embryonic tissue development and has been implicated in the pathogenesis of various human cancers. In this review article, we summarize pre-clinical evidence supporting the suitability of targeting this signaling pathway in cancers. We review agents blocking both the ligand-dependent and ligand-independent cascades, and discuss the clinical evidence, which has led to the FDA approval of Hedgehog receptor Smoothened inhibitors, vismodegib, and sonidegib, in different malignancies. Finally, we provide an overview of published and ongoing clinical trial data on single agent or combination therapeutic strategies, targeting Hedgehog/GLI signaling pathway, in both advanced solid tumors and hematologic malignancies.

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          A paracrine requirement for hedgehog signalling in cancer.

          Robert Yauch, Stephen Gould, Suzie Scales … (2008)
          Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.
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            Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.

            David Berman, Sunil S. Karhadkar, Anirban Maitra … (2003)
            Activation of the Hedgehog (Hh) signalling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is associated with tumorigenesis in skin, the cerebellum and skeletal muscle. Here we show that a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumours in vivo. Unlike in Gorlin's syndrome tumours, pathway activity and cell growth in these digestive tract tumours are driven by endogenous expression of Hh ligands, as indicated by the presence of Sonic hedgehog and Indian hedgehog transcripts, by the pathway- and growth-inhibitory activity of a Hh-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added Hh ligand. Our results identify a group of common lethal malignancies in which Hh pathway activity, essential for tumour growth, is activated not by mutation but by ligand expression.
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              Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.

              R L Yauch, G. J. P. Dijkgraaf, B Alicke … (2009)
              The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.
              Article 0 comments Cited 208 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 29 April 2019
                Publication date Collection: May 2019
                Volume: 8
                Issue: 5
                Electronic Location Identifier: 394
                Affiliations
                [1 ]Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA; xie.hao@ 123456mayo.edu (H.X.); ma.wen@ 123456mayo.edu (W.W.M.)
                [2 ]Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.; paradise.brooke@ 123456mayo.edu
                Author notes
                [* ]Correspondence: fernandezzapico.martin@ 123456mayo.edu ; Tel.: +1-507-255-0285
                Author information
                https://orcid.org/0000-0002-9640-4055
                Article
                Publisher ID: cells-08-00394
                DOI: 10.3390/cells8050394
                PMC ID: 6562674
                PubMed ID: 31035664
                SO-VID: 2900f6e9-3a0e-415b-a690-13f89829c969
                Copyright © © 2019 by the authors.
                License:

                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/).

                History
                Date received : 21 March 2019
                Date accepted : 25 April 2019
                Categories
                Subject: Review

                Keywords: hedgehog,smoothened,gli factors,clinical trials,vismodegib,sonidegib
                Data availability:
                Keywords: hedgehog, smoothened, gli factors, clinical trials, vismodegib, sonidegib

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