Browsing by Subject "Sonidegib"

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    Correction to: Probing the multimodal fungiform papilla: complex peripheral nerve endings of chorda tympani taste and mechanosensitive fibers before and after Hedgehog pathway inhibition
    (Springer, 2022) Donnelly, Christopher R.; Kumari, Archana; Li, Libo; Vesela, Iva; Bradley, Robert M.; Mistretta, Charlotte M.; Pierchala, Brian A.; Anatomy, Cell Biology and Physiology, School of Medicine
    This corrects the article "Probing the multimodal fungiform papilla: complex peripheral nerve endings of chorda tympani taste and mechanosensitive fibers before and after Hedgehog pathway inhibition" in Cell Tissue Res, volume 387 on page 225.
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    Probing the multimodal fungiform papilla: complex peripheral nerve endings of chorda tympani taste and mechanosensitive fibers before and after Hedgehog pathway inhibition
    (Springer, 2022) Donnelly, Christopher R.; Kumari, Archana; Li, Libo; Vesela, Iva; Bradley, Robert M.; Mistretta, Charlotte M.; Pierchala, Brian A.; Anatomy, Cell Biology and Physiology, School of Medicine
    The fungiform papilla (FP) is a gustatory and somatosensory structure incorporating chorda tympani (CT) nerve fibers that innervate taste buds (TB) and also contain somatosensory endings for touch and temperature. Hedgehog (HH) pathway inhibition eliminates TB, but CT innervation remains in the FP. Importantly, after HH inhibition, CT neurophysiological responses to taste stimuli are eliminated, but tactile responses remain. To examine CT fibers that respond to tactile stimuli in the absence of TB, we used Phox2b-Cre; Rosa26LSL-TdTomato reporter mice to selectively label CT fibers with TdTomato. Normally CT fibers project in a compact bundle directly into TB, but after HH pathway inhibition, CT fibers reorganize and expand just under the FP epithelium where TB were. This widened expanse of CT fibers coexpresses Synapsin-1, β-tubulin, S100, and neurofilaments. Further, GAP43 expression in these fibers suggests they are actively remodeling. Interestingly, CT fibers have complex terminals within the apical FP epithelium and in perigemmal locations in the FP apex. These extragemmal fibers remain after HH pathway inhibition. To identify tactile end organs in FP, we used a K20 antibody to label Merkel cells. In control mice, K20 was expressed in TB cells and at the base of epithelial ridges outside of FP. After HH pathway inhibition, K20 + cells remained in epithelial ridges but were eliminated in the apical FP without TB. These data suggest that the complex, extragemmal nerve endings within and disbursed under the apical FP are the mechanosensitive nerve endings of the CT that remain after HH pathway inhibition.
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    Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas
    (Dove Press, 2017-03-16) Jain, Sachin; Song, Ruolan; Xie, Jingwu; Department of Pediatrics, IU School of Medicine
    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. Sonidegib, also named Odomzo, is the second Hh signaling inhibitor approved by the FDA to treat BCCs following approval of the first SMO antagonist vismodegib in 2012. What are the major features of sonidegib (mechanism of action; metabolic profiles, clinical efficacy, safety, and tolerability profiles)? Will the sonidegib experience help other clinical trials using Hh signaling inhibitors in the future? In this review, we will summarize current understanding of BCCs and Hh signaling. We will focus on sonidegib and its use in the clinic, and we will discuss ways to improve its clinical application in cancer therapeutics.