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Vismodegib

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https://www.readbyqxmd.com/read/29326074/overcoming-the-resistance-mechanisms-of-smoothened-inhibitors
#1
REVIEW
Xiaochun Dong, Chenglin Wang, Zhongjian Chen, Weili Zhao
Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors...
January 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29320312/targeted-therapy-for-advanced-solid-tumors-on-the-basis-of-molecular-profiles-results-from-mypathway-an-open-label-phase-iia-multiple-basket-study
#2
John D Hainsworth, Funda Meric-Bernstam, Charles Swanton, Herbert Hurwitz, David R Spigel, Christopher Sweeney, Howard Burris, Ron Bose, Bongin Yoo, Alisha Stein, Mary Beattie, Razelle Kurzrock
Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study...
January 10, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29315702/strategies-to-target-the-hedgehog-signaling-pathway-for-cancer-therapy
#3
REVIEW
Minhang Xin, Xinyue Ji, Ladie Kimberly De La Cruz, Suresh Thareja, Binghe Wang
Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma...
January 5, 2018: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29296645/granulation-tissue-masquerading-as-basal-cell-carcinoma-after-treatment-with-vismodegib
#4
Jayson Miedema, Michael O Meyers, Daniel Zedek, Michelle C Roughton, Puneet S Jolly
No abstract text is available yet for this article.
January 2018: JAAD Case Reports
https://www.readbyqxmd.com/read/29278695/carcinogenicity-assessment-of-the-hedgehog-pathway-inhibitor-vismodegib-in-tg-rash2-mice-and-sprague-dawley-rats
#5
Jinze Li, Eric Morinello, Thomas Larsen, Denzil Frost, Ivor Caro, Stephen Gould, Lisa Wong, Angela Hendricks, Noel Dybdal, Donna Dambach, Melissa Schutten
Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0...
December 23, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29274272/the-role-of-the-hedgehog-signaling-pathway-in-cancer-a-comprehensive-review
#6
REVIEW
Ana Marija Skoda, Dora Simovic, Valentina Karin, Vedran Kardum, Semir Vranic, Ljiljana Serman
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, Suppressor of fused homolog, kinesin-7, protein kinase A, and cyclic adenosine monophosphate (AMP)...
December 23, 2017: Bosnian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/29235062/retreatment-with-vismodegib-after-progression-in-advanced-basal-cell-carcinoma-first-time-report-of-a-single-institution-experience
#7
REVIEW
Salvatore Alfieri, Cristiana Bergamini, Roberta Granata, Laura Locati, Lisa Licitra, Paolo Bossi
Retreatment with vismodegib in advanced basal cell carcinoma (BCC) patients who previously discontinued the drug due to disease progression (PD) has not been reported yet. The objective of our report is to determine whether vismodegib is still active when used in BCC patients who progressed during a first vismodegib course (FVC). We conducted a retrospective study on six advanced BCC patients enrolled in a clinical trial (STEVIE, NCT01367665) who discontinued vismodegib due to PD and were then retreated with the same drug...
December 12, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29203435/occurrence-of-vismodegib-induced-cramps-in-the-treatment-of-basal-cell-carcinoma-a-prospective-study-in-30-patients
#8
Edwina Girard, Arnaud Lacour, Henry Abi Rached, Nassima Ramdane, Carole Templier, Véronique Dziwniel, Eve Desmedt, Emilie Le Rhun, Laurent Mortier
No abstract text is available yet for this article.
December 1, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/29199802/skin-eruption-and-cholestatic-hepatic-injury-due-to-vismodegib
#9
Francesco Drago, Ilaria Trave, Yiran Wei, Aurora Parodi
No abstract text is available yet for this article.
December 1, 2017: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
https://www.readbyqxmd.com/read/29164817/regulation-of-hedgehog-signaling-in-cancer-by-natural-and-dietary-compounds
#10
REVIEW
Cheng Bao, Pavel Kramata, Hong Jin Lee, Nanjoo Suh
The aberrant Hedgehog (Hh) signaling induced by mutations or overexpression of the signaling mediators has been implicated in cancer, associated with processes including inflammation, tumor cell growth, invasion and metastasis, as well as cancer stemness. Small molecules targeting the regulatory components of the Hh signaling pathway, especially Smoothened (Smo), have been developed for the treatment of cancer. However, acquired resistance to a Smo inhibitor vismodegib observed in clinical trials suggests that other Hh signaling components need to be explored as potential anticancer targets...
November 21, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29164054/effective-drug-delivery-in-diffuse-intrinsic-pontine-glioma-a-theoretical-model-to-identify-potential-candidates
#11
Fatma E El-Khouly, Dannis G van Vuurden, Thom Stroink, Esther Hulleman, Gertjan J L Kaspers, N Harry Hendrikse, Sophie E M Veldhuijzen van Zanten
Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29132849/treatment-of-vismodegib-associated-muscle-cramps-with-cyclobenzaprine-a-retrospective-review
#12
Yul W Yang, James B Macdonald, Steven A Nelson, Aleksandar Sekulic
No abstract text is available yet for this article.
December 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/29131041/skin-manifestations-of-targeted-antineoplastic-therapy
#13
Onofre Sanmartín
The management of oncology patients has changed significantly over recent years, with the development of new targeted anticancer therapies. Cutaneous adverse effects are among the most frequently observed toxicities with many targeted agents; their intensity can be dose-limiting or lead to the discontinuation of therapy. Tyrosine kinase inhibitors can cause maculopapular rash and hand-foot reaction, whereas papulopustular rash, paronychia, regulatory changes in hair, and dryness are caused by epidermal growth factor receptor inhibitors...
2018: Current Problems in Dermatology
https://www.readbyqxmd.com/read/29111235/genomic-stability-in-syndromic-basal-cell-carcinoma
#14
Audris Chiang, Prajakta D Jaju, Prag Batra, Melika Rezaee, Ervin H Epstein, Jean Y Tang, Kavita Y Sarin
Basal cell cancers (BCCs) are characterized by up-regulation of Hedgehog pathway through loss of Patched1 or activation of Smoothened, and smoothened-inhibitors such as vismodegib are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with Basal Cell Nevus Syndrome (BCNS) harbor germline defects in Patched1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to Smoothened-inhibitors than sporadic BCCs, with minimal development of resistance...
October 27, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29107429/discovery-of-1-3-aryl-4-chlorophenyl-3-p-aryl-urea-derivatives-against-breast-cancer-by-inhibiting-pi3k-akt-mtor-and-hedgehog-signalings
#15
Wenlu Li, Qinsheng Sun, Lu Song, Chunmei Gao, Feng Liu, Yuzong Chen, Yuyang Jiang
PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29102653/combination-vismodegib-and-photodynamic-therapy-for-multiple-basal-cell-carcinomas
#16
Jason M Rizzo, Robert J Segal, Nathalie C Zeitouni
BACKGROUND: Oral vismodegib therapy and photodynamic therapy (PDT) are non-invasive treatments for basal cell carcinoma (BCC) with overlapping utility in widespread BCCs and patients who are poor surgical candidates. There is no published study to date investigating the combination use of PDT with vismodegib to optimize individual response rates. OBJECTIVE: To evaluate the combination of red light PDT and vismodegib therapy in patients with multiple nodular BCCs...
November 1, 2017: Photodiagnosis and Photodynamic Therapy
https://www.readbyqxmd.com/read/29078327/hedgehog-signaling-regulates-ciliary-localization-of-mouse-odorant-receptors
#17
Devendra Kumar Maurya, Staffan Bohm, Mattias Alenius
The ciliary localization of odorant receptors (ORs) is evolutionary conserved and essential for olfactory transduction. However, how the transport of ORs is regulated in mammalian olfactory sensory neurons is poorly understood. Here we demonstrate that odorant responsiveness and OR transport is regulated by the Hedgehog pathway. OR transport is inhibited by conditional gene inactivation of the Hedgehog signal mediator Smoothened (Smo) as well as by systemic administration of the Smo inhibitor vismodegib, a clinically used anticancer drug reported to distort smell perception in patients...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29073584/vismodegib-in-patients-with-advanced-basal-cell-carcinoma-primary-analysis-of-stevie-an-international-open-label-trial
#18
N Basset-Séguin, A Hauschild, R Kunstfeld, J Grob, B Dréno, L Mortier, P A Ascierto, L Licitra, C Dutriaux, L Thomas, N Meyer, B Guillot, R Dummer, P Arenberger, K Fife, A Raimundo, E Dika, N Dimier, A Fittipaldo, I Xynos, J Hansson
BACKGROUND: The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib-a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)-in a patient population representative of clinical practice. Primary analysis data are presented. PATIENTS AND METHODS: Patients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal...
November 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29057423/9q22-3-microdeletion-syndrome-with-multiple-basal-cell-carcinomas-treated-with-vismodegib-three-key-messages-in-one-patient
#19
Alice Kieny, Valérie Kremer, Sophie Scheidecker, Dan Lipsker
No abstract text is available yet for this article.
October 23, 2017: Acta Dermato-venereologica
https://www.readbyqxmd.com/read/29055164/reflectance-confocal-microscopy-identification-of-subclinical-basal-cell-carcinomas-during-and-after-vismodegib-treatment
#20
Caroline Couzan, Elisa Cinotti, Bruno Labeille, Paul Vercherin, Pietro Rubegni, Frédéric Cambazard, Jean Luc Perrot
BACKGROUND: Recently, it has been shown that reflectance confocal microscopy (RCM) could identify subclinical basal cell carcinoma (BCC) during vismodegib treatment of locally-advanced BCC. OBJECTIVES: To evaluate specificity and sensitivity of clinical, dermoscopic and RCM examination for BCC in patients with multiple BCCs treated by vismodegib. METHODS: 94 BCCs had 710 clinical, dermoscopic and RCM examinations during 72 weeks of vismodegib treatment...
October 21, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
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