Hedgehog Signaling Pathway In Cancer Research Articles

The crosstalk between long non-coding RNAs and the hedgehog signaling pathway in cancer.

Hedgehog (Hh) is a conserved signaling pathway that is involved in embryo development as well as adult tissue maintenance and repair in invertebrates and vertebrates. Abnormal activation of this pathway in various types of malignant drug- and apoptosis-resistant tumors has made it a therapeutic target against tumorigenesis. Thus, understanding the molecular mechanisms that promote the activation or inhibition of this pathway is critical. Long non-coding RNAs (lncRNAs), a subclass of non-coding RNAs with a length of > 200 nt, affect the expression of Hh signaling components via a variety of transcriptional and post-transcriptional processes. This review focuses on the crosstalk between lncRNAs and the Hh pathway in carcinogenesis, outlines the broad role of Hh-related lncRNAs in tumor progression, and illustrates their clinical diagnostic, prognostic, and therapeutic potential in tumors.

Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened.

The Hedgehog-GLI (HH-GLI) pathway is a highly conserved signaling that plays a critical role in controlling cell specification, cell–cell interaction and tissue patterning during embryonic development. Canonical activation of HH-GLI signaling occurs through binding of HH ligands to the twelve-pass transmembrane receptor Patched 1 (PTCH1), which derepresses the seven-pass transmembrane G protein-coupled receptor Smoothened (SMO). Thus, active SMO initiates a complex intracellular cascade that leads to the activation of the three GLI transcription factors, the final effectors of the HH-GLI pathway. Aberrant activation of this signaling has been implicated in a wide variety of tumors, such as those of the brain, skin, breast, gastrointestinal, lung, pancreas, prostate and ovary. In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma. Besides the classical canonical ligand-PTCH1-SMO route, mounting evidence points toward additional, non-canonical ways of GLI activation in cancer. By non-canonical we refer to all those mechanisms of activation of the GLI transcription factors occurring independently of SMO. Often, in a given cancer type canonical and non-canonical activation of HH-GLI signaling co-exist, and in some cancer types, more than one mechanism of non-canonical activation may occur. Tumors harboring non-canonical HH-GLI signaling are less sensitive to SMO inhibition, posing a threat for therapeutic efficacy of these antagonists. Here we will review the most recent findings on the involvement of alternative signaling pathways in inducing GLI activity in cancer and stem cells. We will also discuss the rationale of targeting these oncogenic pathways in combination with HH-GLI inhibitors as a promising anti-cancer therapies.

The role of the Hedgehog signaling pathway in cancer: A comprehensive review.

The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling - autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

An exploratory open-label, investigator-initiated study to evaluate the efficacy and safety of combination sonidegib and buparlisib for advanced basal cell carcinomas

To the Editor: Although smoothened inhibitors (SIs) are Food and Drug Administration approved for advanced basal cell carcinomas (aBCCs), over 50% of patients do not respond. 1 Sekulic A. Migden M.R. Basset-Seguin N. et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017; 17: 332 Crossref PubMed Scopus (222) Google Scholar , 2 Lear J.T. Migden M.R. Lewis K.D. et al. Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study. J Eur Acad Dermatol Venereol. August, 28 2017; ([Epub ahead of print])https://doi.org/10.1111/jdv.14542 Crossref Scopus (121) Google Scholar Preclinical work in models of hedgehog-dependent tumors has revealed the importance of phosphoinositide-3-kinase (PI3K) in promoting SI resistance, 3 Gonnissen A. Isebaert S. Haustermans K. Targeting the hedgehog signaling pathway in cancer: beyond smoothened. Oncotarget. 2015; 6: 13899-13913 Crossref PubMed Scopus (149) Google Scholar , 4 Buonamici S. Williams J. Morrissey M. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010; 2: 51ra70 Crossref PubMed Scopus (388) Google Scholar , 5 Rajurkar M. De Jesus-Monge W.E. Driscoll D.R. et al. The activity of GLI transcription factors is essential for KRAS-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2012; 109: E1038-E1047 Crossref PubMed Scopus (105) Google Scholar , 6 Zhou J. Zhu G. Huang J. et al. Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: a novel potential therapeutic target. Cancer Lett. 2016; 370: 313-323 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar with concurrent smoothened and PI3K inhibition delaying SI resistance in medulloblastoma 4 Buonamici S. Williams J. Morrissey M. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010; 2: 51ra70 Crossref PubMed Scopus (388) Google Scholar (Supplemental Fig 1; available at http://www.jaad.org). 1 Sekulic A. Migden M.R. Basset-Seguin N. et al. Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study. BMC Cancer. 2017; 17: 332 Crossref PubMed Scopus (222) Google Scholar , 3 Gonnissen A. Isebaert S. Haustermans K. Targeting the hedgehog signaling pathway in cancer: beyond smoothened. Oncotarget. 2015; 6: 13899-13913 Crossref PubMed Scopus (149) Google Scholar , 4 Buonamici S. Williams J. Morrissey M. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010; 2: 51ra70 Crossref PubMed Scopus (388) Google Scholar , 5 Rajurkar M. De Jesus-Monge W.E. Driscoll D.R. et al. The activity of GLI transcription factors is essential for KRAS-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2012; 109: E1038-E1047 Crossref PubMed Scopus (105) Google Scholar , 6 Zhou J. Zhu G. Huang J. et al. Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: a novel potential therapeutic target. Cancer Lett. 2016; 370: 313-323 Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar , 7 Chang A.L.S. Oro A.E. Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch Dermatol. 2012; 148: 1324-1325 Crossref PubMed Scopus (150) Google Scholar Due to the lack of good treatment options available to SI-resistant aBCC patients, this open-label, single-arm, proof-of-concept study of combined hedgehog and PI3K inhibition on aBCCs was explored using sonidegib, an SI, and buparlisib, a pan-PI3K inhibitor.

Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened.

An essential role for Hedgehog (Hh) signaling in human cancer has been established beyond doubt. At present, targeting Hh signaling has mainly been investigated with SMO inhibitors. Unfortunately, resistance against currently used SMO inhibitors has already been observed in basal cell carcinoma (BCC) patients. Therefore, the use of Hh inhibitors targeting the signaling cascade more downstream of SMO could represent a more promising strategy. Furthermore, besides the classical canonical way of Hh signaling activation, non-canonical activation of the GLI transcription factors by multiple important signaling pathways (e.g. MAPK, PI3K, TGFβ) has also been described, pinpointing the importance of targeting the transcription factors GLI1/2. The most promising agent in this context is probably the GLI1/2 inhibitor GANT61 which has been investigated preclinically in numerous tumor types in the last few years. In this review, the emerging role of Hh signaling in cancer is critically evaluated focusing on the potential of targeting Hh signaling more downstream of SMO, i.e. at the level of the GLI transcription factors. Furthermore, the working mechanism and therapeutic potential of the most extensively studied GLI inhibitor in human cancer, i.e. GANT61, is discussed in detail. In conclusion, GANT61 appears to be highly effective against human cancer cells and in xenograft mouse models, targeting almost all of the classical hallmarks of cancer and could hence represent a promising treatment option for human cancer.

Abstract CN06-04: The hedgehog signaling pathway in cancer.

Abstract CN06-04: The hedgehog signaling pathway in cancer.

The Hedgehog Signaling Pathway in Cancer

The Hedgehog Signaling Pathway in Cancer

The Hedgehog Signaling Pathway in Cancer

The Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is crucial for proper development. At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. Hh signaling is most active during embryogenesis, and aberrant reactivation of the pathway in adult tissue can lead to the development of cancer. A comprehensive understanding of Hh signaling during development will undoubtedly shed light into the mechanism of Hh in cancer progression and identify potential targets for therapeutic intervention.