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Hedgehog
Hedgehog
Hedgehog(6)

The Hh (Hedgehog) signaling pathway functions in embryo develop, and remains important in adults.(1) The Hh pathway is critical for maintaining tissue polarity and stem cell population.(2) Sonic Hh has been shown to promote the proliferation of adult stem cells from various tissues, including primitive hematopoietic cells, mammary, and neural stem cells. The mammalian Hh pathway is initiated by Sonic Hh, Indian Hh, and Desert Hh.(3) The Hh pathway is highly conserved between invertebrates and mammalian species.(4,13,14) When Sonic Hh reaches its target cell, it binds to the PTCH-1 receptor.(1)
Activation of the Hh pathway has been implicated in the development of cancers in various organs, including brain, SCLC, BC, PC, and skin.(1) The most common way to target this pathway is modulate SMO.(1) The major breakthrough in our understanding of Hh signaling in human cancers came from the discovery that mutations of PTCH1 are associated with a rare hereditary form of BCC-Basal Cell Nevus Syndrome.(2) In the absence of ligand, PTCH1 inhibits SMO, a downstream protein in the pathway. Upon binding of a Hh protein or a mutation in the SSD of PTCH the pump is turned off allowing oxysterols to accumulate around SMO.(1) In addition to PTCH1, mammals have another Hh receptor PTCH2. All three mammalian Hhs bind both receptors with similar affinity. PTCH2 is expressed at much higher levels in the testis and mediates desert Hh signaling there. It appears to have a distinct downstream signaling role from PTCH1. In the absence of ligand binding PTCH2 has a decreased ability to inhibit the activity of SMO.(1)
The most clinically advanced SMO targeting agents are cyclopamine-competitive.(1) Activation of the PI3K/AKT and MAPk cascade is the major intracellular signaling event in response to EGFR stimulation. Both pathways affect the activity of GLI transcription factors.(4) A number of small molecule inhibitors of the essential pathway effector SMO have been identified as potent anti-cancer agents in preclinical models.(4, 5)

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References

1. Lüftner D HP PK. Clinical value of bisphosphonates in cancer therapy. . Anticancer Res. 2007;27(4A):1759-68. PMCID: 17649770.

2. J. X. Implications of hedgehog signaling antagonists for cancer therapy. Acta Biochim Biophys Sin (Shanghai). 2008;40(7):670-80. PMCID: 18604459.

3. Carpenter RL, Lo H-W. Hedgehog pathway and GLI1 isoforms in human cancer. Discovery medicine. 2012;13(69):105.

4. Mangelberger D, Kern D, Loipetzberger A, Eberl M, Aberger F. Cooperative hedgehog-EGFR signaling. Frontiers in bioscience (Landmark edition). 2012;17:90.

5. Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends in pharmacological sciences. 2009;30(6):303-12.

6. Sun S, Schiller JH, Spinola M, Minna JD. New molecularly targeted therapies for lung cancer. The Journal of clinical investigation. 2007;117(10):2740-50.

7. Weinberg R. The biology of cancer: Garland Science; 2013.



News
Monday, September 19, 2016 1:06 PM|Tukachinsky, H., Petrov, K., Watanabe, M., Salic, A.|PNAS - RSS feed of Early Edition articles|Labels: Hh/SMO
The Hedgehog cell–cell signaling pathway is crucial for animal development, and its misregulation is implicated in numerous birth defects and cancers. In unstimulated cells, pathway activity is inhibited by the tumor suppressor membrane protein, Patched. Hedgehog signaling is triggered by the secreted Hedgehog ligand, which binds and inhibits Patched, thus...
Thursday, September 15, 2016 6:45 AM|Li, P., Lee, E. H., Du, F., Gordon, R. E., Yuelling, L. W., Liu, Y., Ng, J. M. Y., Zhang, H., Wu, J., Korshunov, A., Pfister, S. M., Curran, T., Yang, Z.-j.|Cancer Research current issue|Labels: Hh/SMO
The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem–like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here, we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation, resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway–driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Cancer Res; 76(18); 5573–83. ©2016 AACR.
Wednesday, September 14, 2016 6:37 PM|Oncology|Labels: Hh/SMO, Notch, WNT
The cancer stem cell (CSC) theory is current strategy of cancer treatment. Cancers follow pathways of cancer stem cell such as Notch, Wnt and Hedgehog can be addressed with natural products or synthetic drugs to diminish the chance of new tumours. The cancer growth can also be suppressed by aiming the tumourigenic stem cells alone, instead of targeting at reducing complete tumour dimension. The recurrence of tumours after years of disease-free survival has prompted interest in the concept that cancers may have a stem cell basis. Current assumption holds that < 5% of the tumour mass may be chemo-resistant and radio-resistant, harbouring stem-like properties that impel tumour survival, development, and metastasis. There is intense an investigation to interpret CSCs based on self-renewal and multi-lineage differentiation. Nevertheless, no successful targeted therapies have reached the clinic. The ionophore antibiotic salinomycin that selectively kills breast CSCs seems to be a promising anticancer drug. Clinical trials conducted by the NIH (National Institute of Health) on several synthetic drugs demonstrate the current importance of the issue and predict a bright future for such molecular weapons against cancer.
Wednesday, September 14, 2016 7:55 AM|DO CARMO, N. G., SAKAMOTO, L. H. T., POGUE, R., DO COUTO MASCARENHAS, C., PASSOS, S. K., FELIPE, M. S. S., DE ANDRADE, R. V.|Anticancer Research recent issues|Labels: Hh/SMO, WNT

Background/Aim: Nodular and superficial are the most common subtypes of basal cell carcinoma (BCC). Signaling pathways such as Hedgehog (HH) and Wingless (WNT) signaling are associated with BCC phenotypic variation. The aim of the study was to evaluate of the expression profiles of 84 genes related to the WNT and HH signaling pathways in patients with nodular and superficial BCC. Materials and Methods: A total of 58 BCCs and 13 samples of normal skin were evaluated by quantitative real-time polymerase chain reaction (qPCR) to detect the gene-expression profile. Results: qPCR array showed segregation in BCC subtypes compared to healthy skin. PRKX, WNT3 and WNT16 were significantly (p<0.05) altered: PRKX was up-regulated, and WNT3 and WNT16 were down-regulated in nodular BCC. Conclusion: PRKX, WNT3 and WNT16 genes, belonging to the WNT signaling pathway, are involved in the tumorigenic process of nodular BCC.

Tuesday, September 13, 2016 11:38 PM|Feng Wang, Ling Ma, Zhengkui Zhang, Xiaoran Liu, Hongqiao Gao, Yan Zhuang, Pei Yang, Marko Kornmann, Xiaodong Tian, Yinmo Yang|Journal of Cancer|Labels: Hh/SMO, pancreatic cancer

Hedgehog (Hh) signaling is crucially involved in tumorigenesis. This study aimed to assess the role of Hh signaling in the regulation of epithelial-mesenchymal transition (EMT), stemness properties and chemoresistance of human pancreatic Panc-1 cancer stem cells (CSCs). Panc-1 cells were transfected with recombinant lentiviral vectors to silence SMO and serum-free floating-culture system was used to isolate Panc-1 tumorspheres. The expression of CSC and EMT markers was detected by flow cytometry, real-time RT-PCR and Western blot analysis. Malignant behaviors of Panc-1 CSC were evaluated by tumorigenicity assays and nude mouse lung metastasis model. We found that tumorspheres derived from pancreatic cancer cell line Panc-1 possessed self-renewal, differentiation and stemness properties. Hh pathway and EMT were active in Panc-1 tumorspheres. Inhibition of Hh signaling by SMO knockdown inhibited self-renewal, EMT, invasion, chemoresistance, pulmonary metastasis, tumorigenesis of pancreatic CSCs. In conclusion, Hh signaling contributes to the maintenance of stem-like properties and chemoresistance of pancreatic CSC and promotes the tumorigenesis and metastasis of pancreatic cancer. Hh pathway is a potential molecular target for the development of therapeutic strategies for pancreatic CSCs.

Wednesday, August 31, 2016 6:00 PM|Anne Lynn S. Chang, Sarah T. Arron, Michael R. Migden, James A. Solomon, Simon Yoo, Bann-Mo Day, Edward F. McKenna and Aleksandar Sekulic|Articles: MD Anderson Cancer Center|Labels: Hh/SMO
Aberrant activation of the Hedgehog (Hh) pathway is a key driver in the pathogenesis of basal cell carcinomas (BCCs), including patients with BCC nevus syndrome (BCCNS). It is unclear whether BCCs arising in p...
Monday, August 29, 2016 6:00 PM|Davide D’Amico, Gianluca Canettieri|Trends in Molecular Medicine|Labels: Hh/SMO
Developmental Hedgehog (Hh) signaling is found deregulated in a broad spectrum of human malignancies and, thus, is an attractive target for cancer therapy. Currently available Hh inhibitors have shown the rapid occurrence of drug resistance, due to altered signaling in collateral pathways. Emerging observations suggest that Hh signaling regulates protein translation in pathways that depend both on Cap- and IRES-mediated translation. In addition, translational regulators have been shown to modulate Hh function.
Thursday, July 28, 2016 7:56 AM|Pitarresi, J. R., Ostrowski, M. C.|Cancer Research recent issues|Labels: Hh/SMO, pancreatic cancer
Purpose of Study: Pancreatic cancer is an overwhelming fatal disease with less than 5% of patients surviving beyond 5 years. The most prominent histopathological hallmark of pancreatic cancer is its uniquely dense stromal reaction as evidenced by recent reports that highlight the significant role of stromal fibroblasts on pancreatic tumor cell biology. We used novel mouse models to show that genetic inactivation of Smoothened (Smo) in stromal fibroblasts accelerated Kras-initiated tumorigenesis.Research Method: We used a genetically engineered mouse model of pancreatic cancer that relies on constitutive activation of the Kras oncogene in the epithelium. We simultaneously employed cre-loxP technology to conditionally delete Smo exclusively in the fibroblast compartment of the pancreas, thus disrupting the crucial hedgehog paracrine signaling loop between pancreatic tumor cells and fibroblasts.Novel Findings: We showed that deletion of Smo in stromal fibroblasts accelerated pancreatic tumorigenesis through a mechanism involving destabilization of fibroblast PTEN protein. Down-regulation of PTEN enhanced TGF-α production in stromal fibroblasts, and increased epithelial cell transformation and proliferation through epithelial growth factor receptor (EGFR). A selective SMO inhibitor also decreased PTEN in a Kras mouse model as well as in human primary pancreatic cancer associated fibroblasts. Importantly, in pancreatic ductal adenocarcinoma (PDAC) patient samples, low PTEN expression correlated with low SMO expression and with reduced overall survival. These results define a pathway that reprograms stromal fibroblasts from a tumor suppressive phenotype to a tumor promoting phenotype, thus highlighting the dual functions of stromal fibroblasts in pancreatic cancer and the molecular consequences of loss of the hedgehog pathway. Thus, a more comprehensive understanding of tumor-stroma interactions is required to assure effective implementation of targeted therapies.Conclusions and Implications: Recent pre-clinical reports suggest the pancreatic tumor microenvironment functions predominantly to inhibit tumor growth, challenging the concept of tumor stroma as a therapeutic target. Our results provide molecular insight into how the balance between the opposing activities of tumor stromal fibroblasts is maintained, and potentially identifies targets for restoring stromal tumor suppressive functions. In summary, we demonstrate that ablation of paracrine hedgehog signaling in SMA-positive fibroblasts leads to proteasome-mediated degradation of the PTEN tumor suppressor protein and subsequent activation of oncogenic pathways.Citation Format: Jason R. Pitarresi, Michael C. Ostrowski. Genetic ablation of Smoothened in tumor-associated fibroblasts promotes pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A40.
Thursday, July 28, 2016 4:35 AM|Hironobu Minami, Yuichi Ando, Brigette Buig Yue Ma, Jih-Hsiabg Lee, Hiroyuki Momota, Yutaka Fujiwara, Leung Li, Koichi Fukino, Koji Ito, Takeshi Tajima, Asuka Mori, Chia-Chi Lin|Cancer Science|Labels: Hh/SMO, clinical trial
Sonidegib is a selective inhibitor of smoothened receptor, which is a key regulator of hedgehog signaling pathway. The purpose of this study is to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, 2-group, parallel, dose-escalation, phase 1 study conducted in Asian patients (patient group in Japan [group 1] and patient group in Hong Kong and Taiwan [group 2]). Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 had 21 patients (12 treated with 400 mg qd [once daily] and 9 treated with 600 mg qd), whereas group 2 had 24 patients (12 treated with 400 mg qd, 8 treated with 600 mg qd, and 4 treated with 800 mg qd). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in group 1 and group 2 were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg qd was defined in both groups. Difference in tolerability was noted between the East Asian population and Western population. The RD in East Asian patients (400 mg qd) was lower than Western patients (800 mg qd and 250 mg twice daily). Clinicaltrials. gov: [NCT01208831] This article is protected by copyright. All rights reserved.
Wednesday, July 27, 2016 11:11 AM|YAMASAKI, A., ONISHI, H., IMAIZUMI, A., KAWAMOTO, M., FUJIMURA, A., OYAMA, Y., KATANO, M.|Anticancer Research recent issues|Labels: Hh/SMO, pancreatic cancer

Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ-induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor.

Tuesday, May 17, 2016 2:00 AM|Dalila Sellami|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: Hh/SMO

Exposure‐response Analysis of Sonidegib (LDE225), an Oral Inhibitor of the Hedgehog Signaling Pathway, for Effectiveness and Safety in Patients with Advanced Solid Tumors
Jocelyn Zhou Michelle Quinlan, Eunju Hurh, Dalila Sellami
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. -
Sonidegib selectively inhibits smoothened protein, suppresses the growth of Hedgehog pathway‐dependent tumors, and has recently been approved in the indication of locally advanced basal cell carcinoma. A comprehensive exposure‐response analysis was conducted to further characterize the relationship of sonidegib exposure to efficacy and safety. Minimum observed plasma concentration at pre‐dose (Cmin), peak concentration (Cmax), and area under the curve were used as exposure endpoints. Exposure‐efficacy analyses included data from 190 patients who received sonidegib 200 mg or 800 mg once daily in the primary efficacy study. Objective response rate (ORR) (complete response [CR] or partial response [PR]), progression‐free survival (PFS), and time to tumor response (TTR) were assessed by logistic regression, Cox regression and Kaplan‐Meier analyses. Exposure‐safety (creatine phosphokinase [CK] elevation) analyses included data from 336 patients pooled from four clinical trials and included doses across ranges of 100–3000 mg once daily and 250–750 mg twice daily. Similar plasma exposure was observed between responders and non‐responders. The logistic regression model of Week 5 Cmin vs. ORR indicated no relationship between sonidegib exposure resulting from 200 mg or 800 mg doses and the probability of CR or PR. A similar conclusion of no exposure‐efficacy relationship was drawn from the PFS and TTR analyses. Increased exposure was associated with a greater risk of Grade 3 or 4 CK elevation, with lower risk in females than in males when using Cmin in the model. These analyses support the sonidegib dose recommendation for registration and are consistent with clinical observations. This article is protected by copyright. All rights reserved

Saturday, March 26, 2016 10:28 PM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: Hh/SMO, lung cancer
In conclusion, this study showed that HH pathway is a survival signaling that drives LAC cell growth under stress conditions, and HHIP is a key regulator to block the induction of HH pathway. Targeting the HH pathway through inhibitors or HHIP thus holds promise to address EGFR-TKI resistance in LAC in clinic. PMID: 27015549 [PubMed - as supplied by publisher] (Source: Oncotarget)
Sunday, February 14, 2016 5:00 PM|Hui-Wen Lo|Cancers|Labels: Hh/SMO
The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.