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Vismodegib

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https://www.readbyqxmd.com/read/28887802/small-molecule-inhibitors-of-the-hedgehog-pathway-in-the-treatment-of-basal-cell-carcinoma-of-the-skin
#1
REVIEW
Rebecca Danhof, Karl Lewis, Mariah Brown
Basal cell carcinoma (BCC) is the most common type of skin cancer, with rising incidence rates primarily attributed to an aging population and ultraviolet radiation exposure. While the majority of BCCs are localized and respond to standard therapies, a very small minority of these tumors become locally destructive or metastasize. These advanced BCCs may not be amenable to localized treatment with surgery and/or radiation therapy. Most BCCs result from mutations in key receptors in the Hedgehog (HH) signaling pathway...
September 8, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28881358/ligand-dependent-hedgehog-pathway-activation-in-rhabdomyosarcoma-the-oncogenic-role-of-the-ligands
#2
A Almazán-Moga, P Zarzosa, C Molist, P Velasco, J Pyczek, K Simon-Keller, I Giralt, I Vidal, N Navarro, M F Segura, A Soriano, S Navarro, O M Tirado, J C Ferreres, A Santamaria, R Rota, H Hahn, J Sánchez de Toledo, J Roma, S Gallego
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. METHODS: The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304)...
September 7, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28865507/-gorlin-goltz-syndrome-diagnosis-and-treatment-options
#3
João Mendes-Abreu, Miguel Pinto-Gouveia, Cátia Tavares-Ferreira, Ana Brinca, Ricardo Vieira
The Gorlin-Goltz syndrome is a rare autosomal dominant hereditary condition, with complete penetrance and variable expressivity. Characterized by the appearance of multiple basaliomas, and often the development of keratocyst, it can also express itself by the presence of palmar/plantar depressions, calcification of brain sickle, and skeletal birth defects, although less frequently. This article presents two cases involving direct relatives, referred after the identification of several basaliomas and jaw cysts...
May 31, 2017: Acta Médica Portuguesa
https://www.readbyqxmd.com/read/28863112/disruption-of-hedgehog-signaling-by-vismodegib-leads-to-cleft-palate-and-delayed-osteogenesis-in-experimental-design
#4
Shixian Zhang, Chengyong Wang, Changfu Xie, Yongzhen Lai, Di Wu, Guowu Gan, Weihui Chen
The function of hedgehog signaling has previously been shown to be crucial for craniofacial development. In this study, we treated C57/BL6J mice with the hedgehog pathway inhibitor vismodegib by oral gavage to establish a stable vismodegib-induced cleft palate model. At E10.5 and E12.5, mice in the experimental group were treated with 100 mg/kg of vismodegib, whereas mice in the control group were treated with solvent. The treated pregnant mice were sacrificed on E13.5, E14.5, E15.5, and E16.5. Palatal shelf growth was evaluated via histological and immunohistochemical analyses as well as palatal organ culture...
September 2017: Journal of Craniofacial Surgery
https://www.readbyqxmd.com/read/28831360/vismodegib-for-locally-advanced-periocular-and-orbital-basal-cell-carcinoma-a-review-of-15-consecutive-cases
#5
Kai Yuen Wong, Kate Fife, John T Lear, Richard D Price, Amer J Durrani
Basal cell carcinoma (BCC) is the most common periocular skin cancer and can lead to significant morbidity. We assess the effectiveness of vismodegib, a first-in-class Hedgehog signaling pathway inhibitor, in the management of periocular and orbital BCCs based on clinical response, tolerability, and orbital content preservation. All patients with periocular or orbital BCCs who met criteria for vismodegib treatment were recruited prospectively between May 2012 and 2014 from 2 hospitals. Patients received oral vismodegib (150 mg daily) until disease progression, unacceptable toxicity, or withdrawal...
July 2017: Plastic and Reconstructive Surgery. Global Open
https://www.readbyqxmd.com/read/28799948/anticancer-drugs-and-the-regulation-of-hedgehog-genes-gli1-and-ptch1-a-comparative-study-in-nonmelanoma-skin-cancer-cell-lines
#6
Uffe H Olesen, Sophie Bojesen, Julie Gehl, Merete Haedersdal
Nonmelanoma skin cancer is the most common cancer in humans, comprising mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC proliferation is highly dependent on the Hedgehog signaling pathway. We aimed to investigate a panel of anticancer drugs with known activity against skin cancer for their therapeutic potential in localized, enhanced topical treatment of SCC and BCC. Cytotoxicity profiles for vismodegib, 5-fluorouracil (5-FU), methotrexate (MTX), cisplatin, bleomycin, and vorinostat were established in terms of half maximal inhibitory concentration values in a panel of immortalized keratinocytes (HaCaT), BCC (UWBCC1 and BCC77015), and SCC (A431 and SCC25) cell lines...
August 9, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28780365/risk-of-cutaneous-squamous-cell-carcinoma-after-treatment-of-basal-cell-carcinoma-with-vismodegib
#7
Tina Bhutani, Michael Abrouk, Camelia S Sima, Natalia Sadetsky, Jeannie Hou, Ivor Caro, Mary-Margaret Chren, Sarah T Arron
BACKGROUND: Vismodegib is a first-in-class agent targeting the hedgehog signaling pathway for treatment of patients with locally advanced basal cell carcinoma (BCC) and metastatic BCC. There have been concerns about the development of squamous cell carcinoma (SCC) in patients treated with this drug. OBJECTIVE: We sought to determine whether treatment with vismodegib is associated with an increase in the risk of cutaneous SCC. METHODS: In this retrospective cohort study, patients treated with vismodegib as part of phase I and II clinical studies were compared with participants from the University of California, San Francisco, Nonmelanoma Skin Cancer Cohort who received standard therapy for primary BCC...
October 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28758746/palladium-catalyzed-ortho-selective-c-h-chlorination-of-benzamide-derivatives-under-anodic-oxidation-conditions
#8
Miki Konishi, Kazuya Tsuchida, Katsuya Sano, Takuya Kochi, Fumitoshi Kakiuchi
The palladium-catalyzed ortho-selective chlorination of N-quinolinylbenzamide derivatives with hydrochloric acid was achieved under anodic oxidation conditions. The use of 5,7-dichloro-8-quinolinyl group as directing group was effective for the selective chlorination, and the reaction was applicable to benzamide derivatives bearing various functional groups. Synthesis of vismodegib was also completed using the palladium-catalyzed electrochemical C-H chlorination in two different steps.
July 31, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28738360/targeting-developmental-pathways-the-achilles-heel-of-cancer
#9
Wolfram C M Dempke, Klaus Fenchel, Peter Uciechowski, Timothy Chevassut
Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development...
July 22, 2017: Oncology
https://www.readbyqxmd.com/read/28714964/inhibition-of-wnt-signaling-attenuates-self-renewal-of-shh-subgroup-medulloblastoma
#10
J Rodriguez-Blanco, L Pednekar, C Penas, B Li, V Martin, J Long, E Lee, W A Weiss, C Rodriguez, N Mehrdad, D M Nguyen, N G Ayad, P Rai, A J Capobianco, D J Robbins
The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures...
July 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28692520/disruption-of-hedgehog-signaling-by-vismodegib-leads-to-cleft-palate-and-delayed-osteogenesis-in-mice
#11
Shixian Zhang, Chengyong Wang, Changfu Xie, Yongzhen Lai, Di Wu, Guowu Gan, Weihui Chen
The function of hedgehog signaling has previously been shown to be crucial for craniofacial development. In this study, we treated C57/BL6J mice with the hedgehog pathway inhibitor vismodegib by oral gavage to establish a stable vismodegib-induced cleft palate model. At E10.5 and E12.5, mice in the experimental group were treated with 100 mg/kg of vismodegib, whereas mice in the control group were treated with solvent. The treated pregnant mice were sacrificed on E13.5, E14.5, E15.5, and E16.5. Palatal shelf growth was evaluated via histological and immunohistochemical analyses as well as palatal organ culture...
July 7, 2017: Journal of Craniofacial Surgery
https://www.readbyqxmd.com/read/28688278/design-synthesis-and-biological-evaluation-of-optimized-phthalazine-derivatives-as-hedgehog-signaling-pathway-inhibitors
#12
Xiuhong Lu, Yuanqiu Peng, Chenglin Wang, Jun Yang, Xiaolong Bao, Qian Dong, Weili Zhao, Wenfu Tan, Xiaochun Dong
We report herein the design and synthesis of a series of optimized phthalazine compounds as novel hedgehog signaling pathway inhibitors. The 4-methylamino-piperidine moiety of Taladegib was replaced by different four, five or six-membered azacycle or azaspirocycle building blocks. The in vitro Gli-luciferase assay results demonstrate that the scaffold hopping in this region afforded significant influences on Hh pathway inhibition. Pyrrolidin-3-amine moiety was found to be the best linker between pharmacophores phthalazine and fluorine substituted benzoyl group...
September 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28680294/carcinoma-ex-pleomorphic-adenoma-case-report-and-options-for-systemic-therapy
#13
N Chooback, Y Shen, M Jones, K Kasaian, M Martin, T Ng, T Thomson, M Marra, J Laskin, C Ho
The most common benign salivary tumour is a pleomorphic adenoma. Transformation to malignancy, carcinoma ex pleomorphic adenoma (cxpa), occurs in 6% of cases. Management focuses on surgical resection and radiotherapy; however, rare cases require systemic management. We present the case of a 60-year-old woman with a cxpa of the left parotid gland who required systemic therapy for locally recurrent disease. Treatment options were guided by the literature concerning malignant salivary gland tumour and by whole-genome and transcriptome sequencing of the tumour...
June 2017: Current Oncology
https://www.readbyqxmd.com/read/28662901/sonic-hedgehog-pathway-inhibition-normalizes-desmoplastic-tumor-microenvironment-to-improve-chemo-and-nanotherapy
#14
Fotios Mpekris, Panagiotis Papageorgis, Christiana Polydorou, Chrysovalantis Voutouri, Maria Kalli, Athanassios P Pirentis, Triantafyllos Stylianopoulos
Targeting the rich extracellular matrix of desmoplastic tumors has been successfully shown to normalize collagen and hyaluronan levels and re-engineer intratumoral mechanical forces, improving tumor perfusion and chemotherapy. As far as targeting the abundant cancer-associated fibroblasts (CAFs) in desmoplastic tumors is concerned, while both pharmacologic inhibition of the sonic-hedgehog pathway and genetic depletion of fibroblasts have been employed in pancreatic cancers, the results between the two methods have been contradictory...
September 10, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28652022/chsy1-promotes-aggressive-phenotypes-of-hepatocellular-carcinoma-cells-via-activation-of-the-hedgehog-signaling-pathway
#15
Chiung-Hui Liu, Chyn-Tair Lan, Jui-Feng Chou, To-Jung Tseng, Wen-Chieh Liao
Abnormal expression of chondroitin sulfate has been found in many types of cancer, while its biological functions in hepatocellular carcinoma (HCC) progression remain uninvestigated. Here, we report that chondroitin sulfate synthase 1 (CHSY1), the enzyme that mediates the polymerization step of chondroitin sulfate, is a critical mediator of malignant character in HCC that acts via modulating the activity of the hedgehog signaling. CHSY1 was up-regulated frequently in HCC where these events were associated with worse histologic grade and poor survival...
September 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28646606/vismodegib-for-recurrent-locally-destructive-basal-cell-carcinoma-in-a-renal-transplant-patient
#16
P Koelblinger, R Dummer, M Laimer, S Hecht, J W Bauer, A Gaggl, A Kugler
Solid organ transplant patients are at an increased risk of developing cutaneous malignancies owing to long-lasting immunosuppression. The strongest increase in incidence (35-fold) has been reported for cutaneous squamous cell carcinoma [1]. Basal cell carcinoma (BCC) may occur even more frequently, especially during the first years after transplantation [2]. The hedgehog-inhibitor vismodegib has been safely used for the treatment of locally advanced or metastatic BCC in immunocompetent patients since 2012 [3]...
June 24, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28640761/commentary-on-development-of-basal-cell-carcinoma-with-squamous-differentiation-during-vismodegib-treatment
#17
Anne Lynn S Chang
No abstract text is available yet for this article.
July 2017: Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et Al.]
https://www.readbyqxmd.com/read/28631369/inoperable-infiltrative-basal-cell-carcinoma-successfully-treated-with-vismodegib
#18
Omid Zargari, Seyyede Zeinab Azimi, Siamak Geranmayeh
Basal cell carcinoma (BCC) is the most common skin cancer but usually has a good prognosis. However, there is a subset of BCC cases with a less favorable prognosis. For patients with locally advanced, recurrent or metastatic BCCs who are not suitable for surgery or radiotherapy, small-molecule drug inhibitors of hedgehog pathway are a new therapeutic opportunity. Here, we present a case of infiltrative BCC with multiple recurrences. Wide excision with reconstructive plastic surgery was performed initially with adjuvant radiotherapy...
July 2017: Dermatologic Therapy
https://www.readbyqxmd.com/read/28626889/from-basal-cell-morphogenesis-to-the-alopecia-induced-by-hedgehog-inhibitors-connecting-the-dots
#19
REVIEW
C Dessinioti, C Antoniou, A J Stratigos
The deciphering of the hedgehog (Hh) signaling pathway implicated in the tumorigenesis of basal cell carcinoma (BCC), led to the development of targeted drug therapies, e.g. the hedgehog pathway inhibitors (HPI), vismodegib and sonidegib. In the skin, physiologic Hh signaling is activated in growing hair follicles, where it is required for proliferation of the epithelium of hair follicles during morphogenesis and for their postnatal growth. The effects of HPI treatment leading to the regression of BCC and the development of alopecia, underpin the central role of the Hh pathway in BCC formation as well as hair cycling...
June 18, 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/28618224/design-synthesis-and-structure-activity-relationship-of-tetrahydropyrido-4-3-d-pyrimidine-derivatives-as-potent-smoothened-antagonists-with-in-vivo-activity
#20
Wenfeng Lu, Yongqiang Liu, Haikuo Ma, Jiyue Zheng, Sheng Tian, Zhijian Sun, Lusong Luo, Jiajun Li, Hongjian Zhang, Zeng-Jie Yang, Xiaohu Zhang
Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its nonlinear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility...
June 30, 2017: ACS Chemical Neuroscience
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