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Vismodegib

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https://www.readbyqxmd.com/read/28714964/inhibition-of-wnt-signaling-attenuates-self-renewal-of-shh-subgroup-medulloblastoma
#1
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
#2
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
#3
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...
June 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28680294/carcinoma-ex-pleomorphic-adenoma-case-report-and-options-for-systemic-therapy
#4
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
#5
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...
June 27, 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
#6
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...
June 23, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28646606/vismodegib-for-recurrent-locally-destructive-basal-cell-carcinoma-in-a-renal-transplant-patient
#7
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
#8
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
#9
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...
June 19, 2017: Dermatologic Therapy
https://www.readbyqxmd.com/read/28626889/from-basal-cell-morphogenesis-to-the-alopecia-induced-by-hedgehog-inhibitors-connecting-the-dots
#10
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
#11
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
https://www.readbyqxmd.com/read/28607774/a-matching-adjusted-indirect-comparison-of-sonidegib-and-vismodegib-in-advanced-basal-cell-carcinoma
#12
Dawn Odom, Deirdre Mladsi, Molly Purser, James A Kaye, Eirini Palaka, Alina Charter, Jo Annah Jensen, Dalila Sellami
OBJECTIVES: Based on single-arm trial data (BOLT), sonidegib was approved in the US and EU to treat locally advanced basal cell carcinomas (BCCs) ineligible for curative surgery or radiotherapy. Vismodegib, the other approved targeted therapy, also was assessed in a single-arm trial (ERIVANCE). We examined the comparative effectiveness of the two drugs using a matching-adjusted indirect comparison (MAIC) versus an unadjusted indirect comparison. METHODS: After comparing trials and identifying potential prognostic factors, an MAIC was conducted to adjust for differences in key patient baseline characteristics...
2017: Journal of Skin Cancer
https://www.readbyqxmd.com/read/28574612/basal-cell-carcinoma-pathogenesis-and-therapy-involving-hedgehog-signaling-and-beyond
#13
Anshika Bakshi, Sandeep C Chaudhary, Mehtab Rana, Craig A Elmets, Mohammad Athar
Basal cell carcinoma (BCC) of the skin is driven by aberrant hedgehog signaling. Thus blocking this signaling pathway by small molecules such as vismodegib inhibits tumor growth. Primary cilium in the epidermal cells plays an integral role in the processing of hedgehog signaling related proteins. Recent genomic studies point to the involvement of additional genetic mutations that might be associated with the development of BCCs, suggesting significance of other signaling pathways, such as WNT, NOTCH, mTOR, and Hippo, aside from hedgehog in the pathogenesis of this human neoplasm...
June 2, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28565875/smoothened-antagonist-gdc-0449-vismodegib-inhibits-proliferation-and-triggers-apoptosis-in-colon-cancer-cell-lines
#14
Chuanqing Wu, Shaobo Hu, Ji Cheng, Guobin Wang, Kaixiong Tao
The sonic hedgehog (Shh) pathway has been proven to be involved in embryonic development and cancer growth. GDC-0449, an antagonist of the hedgehog signaling receptor Smoothened (Smo), was recently approved by the US Food and Drug Administration as a prescription for skin basal cell carcinoma. However, the efficacy of GDC-0449 in the treatment of colon cancer and other malignancies, such as basal cell carcinoma and pancreatic cancer, has remained to be proven. The present study assessed the effect of GDC-0449 on the colon cancer cell lines Caco-2 and Ht-29...
May 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28546761/spotlight-on-vismodegib-in-the-treatment-of-basal-cell-carcinoma-an-evidence-based-review-of-its-place-in-therapy
#15
REVIEW
Zoe Apalla, Chrysoula Papageorgiou, Aimilios Lallas, Elena Sotiriou, Elizabeth Lazaridou, Efstratios Vakirlis, Athanassios Kyrgidis, Demetrios Ioannides
Vismodegib is approved for the treatment of adult patients with metastatic (mBCC) or locally advanced basal cell carcinoma (laBCC) that have recurred following surgery or for those who are not good candidates for surgery (risk/benefit ratio is against patient's benefit, either because of the general condition or because of the expected morbidity from the surgery) or radiation therapy. This article provides an evidence-based review of its current place in therapy. Analytically, the clinical implications in the management of laBCCs and mBCCs and possible new indications, including the neoadjuvant use before surgical excision, are discussed, while in the end, the challenges regarding class-related adverse events and their optimal management are highlighted...
2017: Clinical, Cosmetic and Investigational Dermatology
https://www.readbyqxmd.com/read/28525403/genetic-diseases-associated-with-an-increased-risk-of-skin-cancer-development-in-childhood
#16
Alexander L Fogel, Kavita Y Sarin, Joyce M C Teng
PURPOSE OF REVIEW: Childhood skin cancers are relatively rare and may indicate an underlying genetic disorder. The increasing elucidation of genetic pathways is changing the diagnosis and management of genetic skin cancer susceptibility syndromes. In this review, we provide an overview of genetic conditions that predispose to skin cancer development in childhood and signs that providers should assess when evaluating affected individuals. RECENT FINDINGS: In basal cell nevus syndrome (BCNS), the patched2 (PTCH2) and suppressor of fused (SUFU) genes have been implicated in disease pathogenesis...
August 2017: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/28523596/pharmacokinetics-and-safety-of-vismodegib-in-patients-with-advanced-solid-malignancies-and-hepatic-impairment
#17
Ghassan K Abou-Alfa, Lionel D Lewis, Patricia LoRusso, Michael Maitland, Priya Chandra, Sravanthi Cheeti, Dawn Colburn, Sarah Williams, Brian Simmons, Richard A Graham
PURPOSE: Vismodegib is a Hedgehog pathway inhibitor approved for the treatment of advanced basal cell carcinoma. Currently, the pharmacokinetics (PK) and safety of vismodegib in patients with hepatic dysfunction are unknown and are the objective of this study. METHODS: Patients with advanced solid malignancies and hepatic impairment were enrolled into one of four cohorts: normal [bilirubin (bili) < upper limit of normal (ULN)], mild (ULN < bili ≤ 1...
July 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28511673/long-term-safety-and-efficacy-of-vismodegib-in-patients-with-advanced-basal-cell-carcinoma-final-update-of-the-pivotal-erivance-bcc-study
#18
Aleksandar Sekulic, Michael R Migden, Nicole Basset-Seguin, Claus Garbe, Anja Gesierich, Christopher D Lao, Chris Miller, Laurent Mortier, Dedee F Murrell, Omid Hamid, Jorge F Quevedo, Jeannie Hou, Edward McKenna, Natalie Dimier, Sarah Williams, Dirk Schadendorf, Axel Hauschild
BACKGROUND: In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC...
May 16, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28507440/ocular-basal-cell-carcinoma-a-brief-literature-review-of-clinical-diagnosis-and-treatment
#19
REVIEW
Yingyun Shi, Renbing Jia, Xianqun Fan
Basal cell carcinoma (BCC) is a common malignant tumor throughout the world. One of the known risk factors of BCC is intense exposure to ultraviolet radiation. More than 50% of BCCs of the eyelid initially occur on the lower lid. The gold standard of diagnosis of BCC is histopathology. Treatment options for BCC consist of surgery, vismodegib, radiotherapy and imiquimod. Surgical excision using Mohs micrographic surgery or wide surgical excision with frozen section margin control is the first consideration for treatment of periocular BCC...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28458774/triple-hedgehog-pathway-inhibition-for-basal-cell-carcinoma
#20
Xinyi Yang, Matthew S Dinehart
Vismodegib, a potent inhibitor of the hedgehog pathway, is an effective treatment for advanced basal cell carcinoma. More recently, it has become recognized that other oral and topical medications exist that also inhibit this pathway. Multifocal inhibition has been shown to work more efficaciously than a single pathway inhibition when treating melanocytic tumors. The authors report the successful treatment of a patient with advanced basal cell carcinoma using the combination of vismodegib, itraconazole, and imiquimod, each of which inhibits a different part of the hedgehog pathway...
April 2017: Journal of Clinical and Aesthetic Dermatology
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