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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
During embryonic growth, neural precursor cells generated in the rhombic lip of the dorsal hindbrain migrate along the surface of the cerebellum to form the external granule layer (EGL). The secretion of bone morphogenic proteins (BMPs), such as BMP6, BMP7, and GDF7, encourages further proliferation generating a rich pool of granule cell precursors (GCPs) in the developing EGL [20, 36]. As older cells exit the EGL and migrate through a layer of Purkinje cells, they encounter the Hedgehog pathway ligand, Sonic hedgehog (SHH), a highly conserved embryonic signaling system which binds to its receptor, Patched 1 (PTCH1), expressed on GCPs in the EGL [37, 38]. Downstream effectors include the GLI family of transcription factors (GLI1, GLI2, and GLI3), which activate transcription of genes, such as cyclinD1 (CCND1) and MYC, thereby facilitating GCP proliferation and migration [7, 20, 36, 39]. After post-natal cerebellar development, this pathway goes dormant with the 12-pass transmembrane receptor, PTCH1, keeping the 7-pass transmembrane protein, Smoothened (SMO), in an inactivated state [40]. This, in turn, leads to the sequestration of downstream effectors of the SHH pathway by Suppressor-of-Fused (SUFU), effectively silencing gene expression [7]. Deregulated binding of SHH to PTCH1 releases and constitutively activates SMO which, in turn, inhibits SUFU, leading to release and nuclear translocation of GLI1-3; as a result, aberrant gene transcription is activated, facilitating phenotypic transformation into medulloblastoma [7].
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The mechanism of action of vismodegib involves cyclopamine-competitive antagonism of the SMO receptor, which inhibits overactive SMO signaling and tumor growth driven by mutations in (or elevated levels of) Hh ligands thus causing the GLI1 and GLI2 transcription factors to remain inactive. This, in turn, prevents the expression of tumor-stimulating genes within the Hedgehog pathway. This pathway is pathogenically significant in >90% of BCC tumors, and may have relevance in up to 30% of all human tumors, including prostate, colorectal, ovarian, pancreatic, and gastrointestinal cancers, along with multiple myeloma and some leukemias. In many of these cancer types, the tumor is driven by the production of the Hedgehog protein that is secreted and affects surrounding cells, which are then stimulated to secrete various proteins to benefit tumor growth.
Non-Melanoma Skin Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Irene De Francesco, Sean Whittaker, Stephen L. Morris
Vismodegib is an oral drug that targets the hedgehog signaling pathway, and it was used in the United Kingdom until 2017 to treat patients with Gorlin syndrome. It acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO), which causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with BCC concluded that vismodegib was significantly better than placebo at reducing new BCC lesions (p < 0.001) and at decreasing the sum of the longest diameter of existing lesions (p = 0.003).37 The main reported side effects are loss of taste, muscle cramps, hair loss, weight loss, and rarely, liver dysfunction. Vismodegib was initially licensed in the United Kingdom in August 2013, but it is no longer available via the cancer drug fund since 2017, when National Institute for Health and Care Excellence (NICE) guidelines concluded they could not recommend the drug because of the uncertainty in the evidence and because it was not cost effective.
Patched 1 and C-C Motif Chemokine Receptor 6 Distinguish Heterogeneous T Helper 17 Subsets in Colitic Lamina Propria
Published in Immunological Investigations, 2023
Shengli Pei, Chao Ke, Jiantao Han, Xingwang Xie
The Hedgehog signaling is an evolutionarily conserved pathway playing critical roles in tissue development and homeostasis (Briscoe and Therond 2013). Hedgehog proteins, including Sonic hedgehog (SHH), Indian hedgehog (IHH), and Desert hedgehog (DHH), prompt diverse cellular reactions such as survival, proliferation, and differentiation (Briscoe and Therond 2013). In canonical Hedgehog signaling, hedgehog proteins bind to the receptor Patched 1 (PTCH1), resulting in derepression of Smoothened (SMO) and subsequent dissociation of Gli proteins (Gli1, Gli2, and Gli3) from an inhibitory complex comprising Kinesin Family Member 7 (Kif7) and Suppressor of fused protein (SUFU). Gli proteins are then processed into transcriptional factors and enter the nucleus to trigger the expression of target genes such as Ptch1 and Gli1. The impact of the Hedgehog signaling to mature T lymphocytes remains poorly understood, although previous studies suggest the involvement of the Hedgehog signaling in the activation of and cytokine expression by CD4+ T cells (Stewart et al. 2002), Th2 differentiation (Yanez et al. 2019), and cytotoxic T lymphocyte function (de la Roche ATR et al. 2013). Previous studies have suggested that the Hedgehog signaling drives differentiation and effector function of Th17 cells and is associated with the occurrence and progression of IBD (Hanna et al. 2022, 2022; Lees et al. 2008; Xie et al. 2021).
Inhibition of TGF-β1 on Gli2 expression was promoted by TNF-α in primary leukemia cells
Published in Journal of Receptors and Signal Transduction, 2022
Zhe Li, Shudan Mao, Ning Zhang
Hh signaling leads to activation of Gli proteins, which transcriptionally regulate various target genes that determines Hh-dependent survival. This cascade finally leads to cell cycle entry to maintain self-renewal of stem cells in various tissues [9,10], inhibiting apoptosis [11], modulating tissue polarity [12], and regulating tissue stem cell differentiation [13]. Gli proteins consist of three components, namely Gli1, Gli2, and Gli3 [14]. Gli2 is thought to function upstream of Gli1, and to be the upstream effector of Hh signaling pathway [15], activating Gli1 expression via direct binding to the promoter region [16]. Gli3 is proposed to inhibit the activating functions of all co-expressed Gli genes [17]. Recent studies have proposed that Gli proteins may be crosstalk mediators of signaling pathways [3]. For instance, it is reported that Hh/Smo signaling pathway can cross talk with TGF-β signaling pathway via Gli proteins.
Resveratrol Inhibition of Renal Cancer Stem Cell Characteristics and Modulation of the Sonic Hedgehog Pathway
Published in Nutrition and Cancer, 2021
Hongliang Sun, Taotao Zhang, Rui Liu, Wanshuang Cao, Zhiqiang Zhang, Zhiqi Liu, Weiwei Qian, Dengdian Wang, Dexin Yu, Caiyun Zhong
Hedgehog (Hh) pathway plays an essential role in regulating embryonic development and adult tissue repairs (14, 15). In addition, the Hh pathway is a crucial stem cells signaling pathways involving three homologous genes, namely, Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh) (16, 17). The Shh signaling pathway has drawn research interests as it regulates CSCs. Abnormal activity of the Shh signaling pathway has been connected to adjust CSCs self-renewal, sphere formation, unlimited proliferation, etc. (18). Upon the binding of Shh to PTCH1 (patched receiver), the suppression of Smoothened (SMO) is relieved, subsequently inducing the glioma-associated oncogenes 1–3 (Gli1, Gli2, and Gli3) proteins ultimately translocate to nucleus and operate as transcription factors (19). According to researches, Gli1 has the ability to activate the transcription of Hh certain target gene, and Gli2 acts as a transcriptional activator. Interestingly, Gli3 repress the transcriptional process in this position (20). Evidently, the Shh pathway activation can induce epithelial–mesenchymal transition (EMT) and metastasis, enhance cell proliferation and survival and upregulate markers of CSCs (21). These researches highlight that the involvement of activation of the Shh signaling pathway is engaged in cancer growth, progression, metastasis, and recurrence.