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Sonidegib

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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/28846163/long-term-efficacy-and-safety-of-sonidegib-in-patients-with-locally-advanced-and-metastatic-basal-cell-carcinoma-30-month-analysis-of-the-randomized-phase-2-bolt-study
#2
J T Lear, M R Migden, K D Lewis, A L S Chang, A Guminski, R Gutzmer, L Dirix, P Combemale, A Stratigos, R Plummer, H Castro, T Yi, M Mone, J Zhou, U Trefzer, M Kaatz, C Loquai, R Kudchadkar, D Sellami, R Dummer
BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), 2 difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials. gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013...
August 28, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28789624/hedgehog-inhibitor-sonidegib-potentiates-177-lu-octreotate-therapy-of-got1-human-small-intestine-neuroendocrine-tumors-in-nude-mice
#3
Johan Spetz, Britta Langen, Nils Rudqvist, Toshima Z Parris, Khalil Helou, Ola Nilsson, Eva Forssell-Aronsson
BACKGROUND: (177)Lu-octreotate can be used to treat somatostatin receptor expressing neuroendocrine tumors. It is highly effective in animal models, but clinical studies have so far only demonstrated low cure rates. Hedgehog inhibitors have shown therapeutic effect as monotherapy in neuroendocrine tumor model systems and might be one option to enhance the efficacy of (177)Lu-octreotate therapy. The aim of this study was to determine the therapeutic effect of combination therapy using (177)Lu-octreotate and the Hedgehog signaling pathway inhibitor sonidegib...
August 8, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28738360/targeting-developmental-pathways-the-achilles-heel-of-cancer
#4
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...
2017: Oncology
https://www.readbyqxmd.com/read/28626889/from-basal-cell-morphogenesis-to-the-alopecia-induced-by-hedgehog-inhibitors-connecting-the-dots
#5
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/28607774/a-matching-adjusted-indirect-comparison-of-sonidegib-and-vismodegib-in-advanced-basal-cell-carcinoma
#6
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/28605510/phase-i-study-of-oral-sonidegib-lde225-in-pediatric-brain-and-solid-tumors-and-a-phase-ii-study-in-children-and-adults-with-relapsed-medulloblastoma
#7
Mark W Kieran, Julia Chisholm, Michela Casanova, Alba A Brandes, Isabelle Aerts, Eric Bouffet, Simon Bailey, Sarah Leary, Tobey J MacDonald, Francoise Mechinaud, Kenneth J Cohen, Riccardo Riccardi, Warren Mason, Darren Hargrave, Stacey Kalambakas, Priya Deshpande, Feng Tai, Eunju Hurh, Birgit Geoerger
Background.: Sonidegib (LDE225) is a potent, selective Hedgehog (Hh) inhibitor of SMOOTHENED. This study explored the safety and pharmacokinetics (PK) of sonidegib in children with relapsed/recurrent tumors followed by a phase II trial in pediatric and adult patients with relapsed medulloblastoma (MB) to assess tumor response. Methods.: Pediatric patients aged ≥1-<18 years were included according to a Bayesian design starting at 372mg/m2 of continuous once daily oral sonidegib...
June 9, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28577129/effects-of-mild-to-severe-hepatic-impairment-on-the-pharmacokinetics-of-sonidegib-a-multicenter-open-label-parallel-group-study
#8
Yves Horsmans, Jocelyn Zhou, Mateva Liudmila, George Golor, Oren Shibolet, Michelle Quinlan, Corinne Emotte, Hildegard Boss, Henry Castro, Dalila Sellami, Richard A Preston
BACKGROUND AND OBJECTIVE: Sonidegib is a potent, selective and orally bioavailable inhibitor of the Hedgehog signaling pathway, primarily metabolized by the liver. In order to make dose recommendations for patients with hepatic impairment, we have assessed here the pharmacokinetics (PKs) and safety of sonidegib in subjects with varying degrees of hepatic function. METHODS: The primary objective of this phase I, multicenter, open-label study was to evaluate the PKs of a single oral 800 mg dose of sonidegib in subjects with impaired hepatic function compared with healthy subjects...
June 2, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28560483/conditional-loss-of-hepatocellular-hedgehog-signaling-in-female-mice-leads-to-the-persistence-of-hepatic-steroidogenesis-androgenization-and-infertility
#9
Christiane Rennert, Franziska Eplinius, Ute Hofmann, Janina Johänning, Franziska Rolfs, Wolfgang Schmidt-Heck, Reinhardt Guthke, Rolf Gebhardt, Albert M Ricken, Madlen Matz-Soja
The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism...
May 30, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28416737/efficacy-of-continuous-egfr-inhibition-and-role-of-hedgehog-in-egfr-acquired-resistance-in-human-lung-cancer-cells-with-activating-mutation-of-egfr
#10
Carminia Maria Della Corte, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Vincenza Ciaramella, Teresa Troiani, Erika Martinelli, Valentina Belli, Fortunato Ciardiello, Floriana Morgillo
PURPOSE: The aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors. EXPERIMENTAL DESIGN: We developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib)...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404762/implementation-of-systemic-hedgehog-inhibitors-in-daily-practice-as-neoadjuvant-therapy
#11
REVIEW
Nikki Tang, Desiree Ratner
The most common cancer in both men and women is basal cell carcinoma (BCC). Although most primary and recurrent BCCs have high cure rates with standard therapies, advanced BCCs present a greater treatment challenge, especially in cosmetically and functionally sensitive areas. In patients unable to undergo surgery or radiation therapy, hedgehog inhibitors can be used neoadjuvantly to reduce tumor size, decreasing the extent and complexity of any subsequent surgery and providing either a cure or palliation. The goal of this review is to summarize the pharmacology, efficacy, and safety of systemic hedgehog inhibitors, as well as their role in daily practice as neoadjuvant therapy...
April 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28352196/sonidegib-mechanism-of-action-pharmacology-and-clinical-utility-for-advanced-basal-cell-carcinomas
#12
REVIEW
Sachin Jain, Ruolan Song, Jingwu Xie
The Hedgehog (Hh) pathway is critical for cell differentiation, tissue polarity, and stem cell maintenance during embryonic development, but is silent in adult tissues under normal conditions. However, aberrant Hh signaling activation has been implicated in the development and promotion of certain types of cancer, including basal cell carcinoma (BCC), medulloblastoma, and gastrointestinal cancers. In 2015, the US Food and Drug Administration (FDA) approved sonidegib, a smoothened (SMO) antagonist, for treatment of advanced BCC (aBCC) after a successful Phase II clinical trial...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28317088/phase-i-trial-of-the-oral-smoothened-inhibitor-sonidegib-in-combination-with-paclitaxel-in-patients-with-advanced-solid-tumors
#13
A Stathis, D Hess, R von Moos, K Homicsko, G Griguolo, M Joerger, M Mark, C J Ackermann, S Allegrini, C V Catapano, A Xyrafas, M Enoiu, S Berardi, P Gargiulo, C Sessa
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m(2) on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28182134/differential-pharmacology-and-clinical-utility-of-sonidegib-in-advanced-basal-cell-carcinoma
#14
REVIEW
Mohd Wahid, Arshad Jawed, Sajad Ahmad Dar, Raju K Mandal, Shafiul Haque
Patients suffering from advanced basal cell carcinoma (BCC) have very limited treatment options. Sonidegib selectively inhibits the growth of Hedgehog pathway-dependent tumors and can treat locally advanced BCC patients who are not candidates for surgery or radiation therapy. The BOLT clinical trials were conducted to evaluate the efficacy/potency of sonidegib in the treatment of advanced BCC or metastatic BCC. The patients were randomized in 1:2 ratios to receive 200 or 800 mg oral sonidegib daily, stratified by disease, histological subtype and geographical region...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28122787/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-drug-drug-interactions-of-sonidegib-lde225-with-perpetrators-of-cyp3a-in-cancer-patients
#15
Heidi J Einolf, Jocelyn Zhou, Christina Won, Lai Wang, Sam Rebello
Sonidegib (Odomzo®) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. This data was used to verify a physiologically-based pharmacokinetic (PBPK) model developed to: 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients, 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady-state, and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients...
January 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28073840/fda-approval-summary-sonidegib-for-locally-advanced-basal-cell-carcinoma
#16
Denise Casey, Suzanne Demko, Stacy Shord, Hong Zhao, Huanyu Chen, Kun He, Alexander Putman, Whitney Helms, Patricia Keegan, Richard Pazdur
On July 24, 2015, the FDA approved sonidegib (ODOMZO; Novartis) for the treatment of patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy. The approval was based on data from one randomized, double-blind, noncomparative trial of two doses of sonidegib administered to 230 hedgehog inhibitor-naïve patients with metastatic basal cell carcinoma (mBCC, n = 36) or laBCC (n = 194). Patients were randomized 2:1 to receive sonidegib 800 mg (n = 151) or 200 mg (n = 79) daily...
May 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
#17
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
#18
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
#19
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
https://www.readbyqxmd.com/read/27875522/hedgehog-inhibition-enhances-efficacy-of-radiation-and-cisplatin-in-orthotopic-cervical-cancer-xenografts
#20
Naz Chaudary, Melania Pintilie, David Hedley, Richard P Hill, Michael Milosevic, Helen Mackay
BACKGROUND: The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx). METHODS: 5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models...
January 3, 2017: British Journal of Cancer
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