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https://www.readbyqxmd.com/read/28302010/discovery-of-hedgehog-antagonists-for-cancer-therapy
#1
Harleen Khatra, Chandra Bose, Surajit Sinha
BACKGROUND: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28297142/vismodegib-therapy-for-basal-cell-carcinoma-in-an-8-year-old-chinese-boy-with-xeroderma-pigmentosum
#2
Douglas Fife, Marko A Laitinen, David J Myers, Pamela B Landsteiner
Vismodegib is an oral inhibitor of the Hedgehog signaling pathway and has been used to treat basal cell carcinoma (BCC) in adults. This article reports clearance of a nodular BCC of the nasal tip in an 8-year-old boy with xeroderma pigmentosum (XP). BCC can pose therapeutic challenges when located in areas that are not amenable to traditional therapies such as Mohs micrographic surgery or topical agents. Vismodegib was used at a dose of 150 mg/day to treat the boy's BCC. After 4 months of therapy, we achieved complete clinical clearance...
March 2017: Pediatric Dermatology
https://www.readbyqxmd.com/read/28276480/selective-targeting-of-hdac1-2-elicits-anticancer-effects-through-gli1-acetylation-in-preclinical-models-of-shh-medulloblastoma
#3
Sonia Coni, Anna Barbara Mancuso, Laura Di Magno, Giulia Sdruscia, Simona Manni, Silvia Maria Serrao, Dante Rotili, Eleonora Spiombi, Francesca Bufalieri, Marialaura Petroni, Monika Kusio-Kobialka, Enrico De Smaele, Elisabetta Ferretti, Carlo Capalbo, Antonello Mai, Pawel Niewiadomski, Isabella Screpanti, Lucia Di Marcotullio, Gianluca Canettieri
SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28250200/cxcl14-is-a-candidate-biomarker-for-hedgehog-signalling-in-idiopathic-pulmonary-fibrosis
#4
Guiquan Jia, Sanjay Chandriani, Alexander R Abbas, Daryle J DePianto, Elsa N N'Diaye, Murat B Yaylaoglu, Heather M Moore, Ivan Peng, Jason DeVoss, Harold R Collard, Paul J Wolters, Jackson G Egen, Joseph R Arron
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is associated with aberrant expression of developmental pathways, including Hedgehog (Hh). As Hh signalling contributes to multiple pro-fibrotic processes, Hh inhibition may represent a therapeutic option for IPF. However, no non-invasive biomarkers are available to monitor lung Hh activity. METHODS: We assessed gene and protein expression in IPF and control lung biopsies, mouse lung, fibroblasts stimulated in vitro with sonic hedgehog (SHh), and plasma in IPF patients versus controls, and cancer patients before and after treatment with vismodegib, a Hh inhibitor...
March 1, 2017: Thorax
https://www.readbyqxmd.com/read/28202523/cancer-stem-cells-regulate-cancer-associated-fibroblasts-via-activation-of-hedgehog-signaling-in-mammary-gland-tumors
#5
Giovanni Valenti, Hazel M Quinn, Guus Jje Heynen, Linxiang Lan, Jane D Holland, Regina Vogel, Annika Wulf-Goldenberg, Walter Birchmeier
Many tumors display intracellular heterogeneity, with subsets of cancer stem cells (CSC) that sustain tumor growth, recurrence, and therapy resistance. Cancer associated fibroblasts (CAF) have been shown to support and regulate CSC function. Here we investigated the interactions between CSCs and CAFs in mammary gland tumors driven by combined activation of Wnt/β-catenin and Hgf/Met signaling in mouse mammary epithelial cells. In this setting, CSCs secreted the hedgehog ligand SHH, which regulated CAFs via paracrine activation of Hedgehog signaling...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28196186/statistical-concerns-on-vismodegib-for-basal-cell-carcinoma-meta-analysis
#6
Joao Paulo da Silveira Nogueira Lima
No abstract text is available yet for this article.
February 8, 2017: JAMA Dermatology
https://www.readbyqxmd.com/read/28196183/statistical-concerns-on-vismodegib-for-basal-cell-carcinoma-meta-analysis-reply
#7
Audrey A Jacobsen, John Strasswimmer
No abstract text is available yet for this article.
February 8, 2017: JAMA Dermatology
https://www.readbyqxmd.com/read/28194541/undermining-plastic-surgery-as-a%C3%A2-possible-option-for-treating-basal-cell-carcinoma-of-the-forehead
#8
Georgi Tchernev, Ivan Pidakev, Ilia Lozev, Torello Lotti, Jose Carlos Cardoso, James W Patterson
Basal cell carcinoma (BCC) is the most common cutaneous cancer. Although most cases can be cured with simple surgical procedures and are associated with a good prognosis, a minority of BCCs may pose significant therapeutic challenges. This occurs mostly in cases of so-called advanced BCC, which a loosely defined term that encompasses locally advanced lesions and tumors with metastatic spread. Treatment of these cases is often complex and sometimes may need combinations of therapeutic modalities, including surgery, radiotherapy and/or targeted therapy directed towards sonic hedgehog (SHH) signaling pathways, such as vismodegib...
February 13, 2017: Wiener Medizinische Wochenschrift
https://www.readbyqxmd.com/read/28188087/intermittent-vismodegib-dosing-to-treat-multiple-basal-cell-carcinomas
#9
Klara Mosterd
No abstract text is available yet for this article.
March 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28188086/two-intermittent-vismodegib-dosing-regimens-in-patients-with-multiple-basal-cell-carcinomas-mikie-a-randomised-regimen-controlled-double-blind-phase-2-trial
#10
Brigitte Dréno, Rainer Kunstfeld, Axel Hauschild, Scott Fosko, David Zloty, Bruno Labeille, Jean-Jacques Grob, Susana Puig, Frank Gilberg, Daniel Bergström, Damian R Page, Gary Rogers, Dirk Schadendorf
BACKGROUND: Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas. METHODS: In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas...
February 7, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28135752/-vismodegib-therapy-for-periocular-basal-cell-carcinoma
#11
M Keserü, S Green, S Dulz
Background Basal cell carcinoma (BCC) is the commonest periorbital tumour. Mohs' micrographic surgery and secondary reconstruction is the therapeutic gold standard for periorbital BCC. In cases of inoperability for any reason, therapeutic alternatives are needed. Since the approval of vismodegib, an orally administered, targeted BCC therapy is available. Nevertheless there is little information on the use of vismodegib for periorbital BCC. Patients and Methods In a retrospective study, we analysed the data of 4 patients treated with vismodegib since 2014...
January 2017: Klinische Monatsblätter Für Augenheilkunde
https://www.readbyqxmd.com/read/28114606/a-novel-alternate-dosing-of-vismodegib-for-treatment-of-patients-with-advanced-basal-cell-carcinomas
#12
Lauren R Becker, Angela E Aakhus, Hilary C Reich, Peter K Lee
No abstract text is available yet for this article.
January 18, 2017: JAMA Dermatology
https://www.readbyqxmd.com/read/28110457/reduced-proliferation-and-colony-formation-of-head-and-neck-squamous-cell-carcinoma-hnscc-after-dual-targeting-of-egfr-and-hedgehog-pathways
#13
Hannes Liebig, Georg Günther, Marlen Kolb, Christian Mozet, Andreas Boehm, Andreas Dietz, Gunnar Wichmann
PURPOSE: The hedgehog signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened, and based on molecular data, may prevent resistance to EGFR targeting. METHODS: To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation...
January 21, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28101025/giant-basal-cell-carcinomas-arising-on-the-bilateral-forearms-of-a-patient-a-case-report-and-review-of-nonsurgical-treatment-options
#14
Sarah Shangraw, Rivka C Stone, Jeong Hee Cho-Vega, Robert S Kirsner
Giant basal cell carcinomas (GBCCs) are large basal cell carcinomas (BCCs; <5 cm) with a greater propensity to invade and metastasize than standard BCCs. The presence of 2 GBCCs in a single individual is rare. We present the case of a 71-year-old Caucasian male with bilateral GBCCs on the dorsal forearms, measuring 130 cm(2) and 24 cm(2), respectively, that developed over a 21-year period. Over this period, the patient treated the tumors with herbal remedies. Histologic evaluation showed a conventional nodular BCC for both tumors...
September 2016: Case Reports in Dermatology
https://www.readbyqxmd.com/read/28063021/hepatotoxicity-with-vismodegib-an-md-anderson-cancer-center-and-research-on-adverse-drug-events-and-reports-project
#15
Beatrice J Edwards, Dennis W Raisch, Smita S Saraykar, Ming Sun, Josh A Hammel, Hai T Tran, Nathaniel Wehr, Rasha Arabyat, Dennis P West
BACKGROUND: On 30 January 2012, the US FDA approved vismodegib (Erivedge(®), Genentech, CA, USA) for the management of both metastatic and locally advanced basal cell carcinoma. OBJECTIVE: Our objective was to identify evidence of hepatotoxicity with vismodegib in the FDA Adverse Event Reporting System (FAERS) in treated patients in two National Cancer Institute Comprehensive Cancer Centers. METHODS: FAERS was searched for reports dated 1 January 2009 through 31 December 2015 using terms including hedgehog pathway and vismodegib and hepatic-related terms such as liver, jaundice, and hepatitis, among others...
March 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28002101/development-of-basal-cell-carcinoma-with-squamous-differentiation-during-vismodegib-treatment
#16
Lawrence Feigenbaum, Brian L Scott, Molly S Moye, Rajiv I Nijhawan
No abstract text is available yet for this article.
December 19, 2016: Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et Al.]
https://www.readbyqxmd.com/read/28000572/-vismodegib-for-basal-cell-carcinoma-targeted-therapy-in-case-of-locally-advanced-or-metastasised-disease
#17
M G H C Reinders, J B Terra, A K L Reyners, M J Aarts, E R M de Haas, K Mosterd
The development of the hedgehog pathway inhibitor vismodegib provides a new treatment option for metastasised and locally advanced basal cell carcinoma in which surgical excision or radiotherapy is contraindicated. Only a fraction of patients with basal cell carcinoma are eligible for this therapy, but it is effective in the majority of those who do receive vismodegib. However, development of tumour resistance is quite common and adverse events frequently lead to discontinuation of therapy. Intermittent treatment or combination therapy could reduce the occurrence of tumour resistance and diminish toxicity...
2016: Nederlands Tijdschrift Voor Geneeskunde
https://www.readbyqxmd.com/read/27972507/cost-efffectivenes-of-sonidegib-versus-vismodegib-for-the-treatment-of-patients-with-locally-advanced-basal-cell-carcinoma-not-amenable-to-surgery-or-radiotherapy
#18
M Purser, D Mladsi, J A Kaye
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27942391/metastatic-basal-cell-carcinoma-with-amplification-of-pd-l1-exceptional-response-to-anti-pd1-therapy
#19
Sadakatsu Ikeda, Aaron M Goodman, Philip R Cohen, Taylor J Jensen, Christopher K Ellison, Garrett Frampton, Vincent Miller, Sandip P Patel, Razelle Kurzrock
Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burden (> 50 mutations per megabase; 19 functional alterations in tissue next-generation sequencing (NGS; 315 genes)) as well as PDL1/PDL2/JAK2 amplification (as determined by both tissue NGS and by analysis of plasma-derived cell-free DNA)...
2016: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/27928965/targeting-the-hedgehog-pathway-for-locally-advanced-and-metastatic-basal-cell-carcinoma
#20
Vivian T Yin, Bita Esmaeli
Basal cell caricnoma (BCC), the most common periocular magliancy, is treated with complete surgical excision. However, in patients not amenable to surgery or when surgical resection means loss of vital organs or disfiguring procedures due to locally advanced or metastatic disease, targeting the hedgehog pathway offers a novel treatment approach for such patients. Mutation in PTCH1 and SMO has been identified in patients with basal cell nevoid syndrome as well as in patients with sporadic BCC. Inhibition of SMO by vismodegib or sonidegib, the two sonic hedgehog inhibitor drugs approved by the Food and Drug Administration in the United States, has shown overall response rate for locally advanced and metastatic BCC around 50%...
2017: Current Pharmaceutical Design
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