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      Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

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          Abstract

          Hedgehog inhibitors are promising alternative treatments for patients with advanced basal cell carcinomas. Sonidegib (Odomzo ®), an oral smoothened (SMO) antagonist, is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who present recurrence following surgery or radiation therapy, or those who are not candidates for surgery or radiotherapy. Several studies and randomized controlled trials have been conducted to evaluate the efficacy, safety, and tolerability of this new molecule that has demonstrated a good response rate (44%). Grade 1–2 adverse events have also been reported. Further studies of real-world experiences are needed to better understand the correct management of the drug, alternative dosing regimens, and differences with other hedgehog inhibitors. This article provides a complete overview of the pharmacology and pharmacokinetics of sonidegib and a report of the trials and studies conducted. The most frequent adverse events and their correct management are also discussed.

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          Most cited references35

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          Guidelines for the management of basal cell carcinoma.

          This article represents a planned regular updating of the previous British Association of Dermatologists guidelines for the management of basal cell carcinoma. These guidelines present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.
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            Basal Cell Carcinoma: Part 1

            As the most common human cancer worldwide and continuing to increase in incidence, basal cell carcinoma is associated with significant morbidity and cost. Continued advances in research have refined both our insight and approach to this seemingly ubiquitous disease. This 2-part continuing medical education article will provide a comprehensive and contemporary review of basal cell carcinoma. The first article in this series describes our current understanding of this disease regarding epidemiology, cost, clinical and histopathologic presentations, carcinogenesis, natural history, and disease associations.
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              Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma.

              The malignant brain cancer medulloblastoma is characterized by mutations in Hedgehog (Hh) signaling pathway genes, which lead to constitutive activation of the G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor Smoothened (Smo). The Smo antagonist NVP-LDE225 inhibits Hh signaling and induces tumor regression in animal models of medulloblastoma. However, evidence of resistance was observed during the course of treatment. Molecular analysis of resistant tumors revealed several resistance mechanisms. We noted chromosomal amplification of Gli2, a downstream effector of Hh signaling, and, more rarely, point mutations in Smo that led to reactivated Hh signaling and restored tumor growth. Analysis of pathway gene expression signatures also, unexpectedly, identified up-regulation of phosphatidylinositol 3-kinase (PI3K) signaling in resistant tumors as another potential mechanism of resistance. Probing the relevance of increased PI3K signaling, we demonstrated that addition of the PI3K inhibitor NVP-BKM120 or the dual PI3K-mTOR (mammalian target of rapamycin) inhibitor NVP-BEZ235 to the initial treatment with the Smo antagonist markedly delayed the development of resistance. Our findings may be useful in informing treatment strategies for medulloblastoma.
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                Author and article information

                Contributors
                ali.vil@hotmail.it
                Journal
                Dermatol Ther (Heidelb)
                Dermatol Ther (Heidelb)
                Dermatology and Therapy
                Springer Healthcare (Cheshire )
                2193-8210
                2190-9172
                15 April 2020
                15 April 2020
                June 2020
                : 10
                : 3
                : 401-412
                Affiliations
                GRID grid.4691.a, ISNI 0000 0001 0790 385X, Dermatology Unit, Department of Clinical Medicine and Surgery, , University of Naples Federico II, ; Naples, Italy
                Article
                378
                10.1007/s13555-020-00378-8
                7211768
                32297221
                b3af504b-726e-4311-8185-56dadc02904c
                © The Author(s) 2020
                History
                : 17 March 2020
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                Dermatology
                adverse events,basal cell carcinoma,hedgehog inhibitors,sonidegib
                Dermatology
                adverse events, basal cell carcinoma, hedgehog inhibitors, sonidegib

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