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Hedgehog Pathway Inhibition for the Treatment of Basal Cell Carcinoma

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Abstract

Globally, basal cell carcinoma is the most commonly diagnosed cancer. While most cases are amenable to surgery, treatment options for advanced basal cell carcinoma, including locally advanced basal cell carcinoma and metastatic basal cell carcinoma, have proved more difficult. Recent advances regarding the role of hedgehog signaling in the pathogenesis of basal cell carcinoma and the identification of hedgehog pathway inhibitors have facilitated the development of treatment options with improved clinical outcomes. The hedgehog signaling pathway regulates development, cell proliferation, and tissue repair. The pathway is tightly regulated under normal physiological conditions. However, dysregulated hedgehog signaling in human cancers was first described in patients with basal cell carcinoma nevus syndrome and sporadic basal cell carcinoma, in which germline or somatic mutations in pathway components (e.g., smoothened [Smo] and patched-1) lead to constant activation. Subsequently, inhibitors blocking hedgehog signaling either at the level of Smo (i.e., vismodegib, sonidegib, patidegib, and itraconazole) or via an unknown mode of action (arsenic trioxide) were identified. The hedgehog inhibitor vismodegib is approved for the treatment of locally advanced basal cell carcinoma and metastatic basal cell carcinoma while sonidegib is approved for the treatment of locally advanced basal cell carcinoma in the USA and Europe; and for locally advanced basal cell carcinoma and metastatic basal cell carcinoma in Switzerland and Australia. The most common treatment-emergent adverse events associated with approved hedgehog inhibitors include muscle spasms, dysgeusia, and alopecia. This review addresses the challenges associated with appropriately diagnosing locally advanced basal cell carcinoma, provides an overview of hedgehog signaling in basal cell carcinoma, and discusses the pharmacology of hedgehog inhibitors and their efficacy, and adverse events associated with hedgehog inhibitor use, and their management.

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Authors and Affiliations

  1. Haut-Tumor-Zentrum Hannover (HTZH), Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule Hannover (MHH), Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Ralf Gutzmer

  2. Ameriderm Research, Ormond Beach, FL, USA

    James A. Solomon

  3. University of Central Florida College of Medicine, Orlando, FL, USA

    James A. Solomon

  4. Florida State University College of Medicine, Tallahassee, FL, USA

    James A. Solomon

  5. Kansas City University of Medicine and Biosciences, Kansas City, MO, USA

    James A. Solomon

  6. University of Illinois College of Medicine, Urbana, IL, USA

    James A. Solomon

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Correspondence to Ralf Gutzmer.

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Funding

This work was funded by Sun Pharmaceutical Industries, Inc., Princeton, NJ, USA. The authors received no compensation for the creation of this review. Medical writing and editorial support were provided by Marie-Louise Ricketts, PhD, of AlphaBioCom, LLC, King of Prussia, PA, USA.

Conflict of interest

Ralf Gutzmer serves as a consultant to Almirall, Amgen, Bristol-Myers Squibb, Incyte, LEO Pharma, Merck Serono, Merck Sharp Dohme, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi Genzyme, Sun Pharmaceutical Industries, Inc., Takeda, and 4SC; has received travel grants and honoraria for lectures from Almirall, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Merck Serono, Merck Sharp Dohme, Novartis, Pierre-Fabre, Roche, and Sun Pharmaceutical Industries, Inc.; and received research funding from Amgen, Johnson & Johnson, Merck-Serono, Novartis, and Pfizer. James A. Solomon serves as consultant to Lilly, Mayne, Sun Pharmaceutical Industries, Inc., and Ameriderm; and has received research funding from Allergan, Altana, Anacor, Apotex, AstraZeneca, Asubio, Barrier, Basilea, Bayer, Boehringer Ingelheim, Biocryst, Braintree, Centocor, Celtic, Chilter, Cipher, Clynsis, Concentrics, Covance, CuTech, Dermira, Dow, Eli Lilly, Encorium, Epithany, Galderma, Genentech, Genomics, GlaxoSmithKline, Glenmark, Health Decisions, HedgePath Pharmaceutical, Hill, ICON, Incyte, Inventiv, Kendle International, LEO Pharmaceuticals, Manhattan, Maruho, MAVIS, Merck, Novartis, Noven, Novum, Omnicare, ParaPro Inc, Parexel, Peplin, Pfizer, PharmaNet, Polynoma, PPD Development, PRA, Premier, Pro Trials, Quintiles, Regeneron, Research Sample Bank, Rho, Roche, Sanofi-Aventis, SciQuus, Serentis, SGS, Steifel, Sterling Bio, Symbio, Taisho, Taro, Teva Pharmaceutical, Theraputics Clinical Research, TKL Research, Tolmar, Topaz, Vanda, and Worldwide Clinical Trials.

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Gutzmer, R., Solomon, J.A. Hedgehog Pathway Inhibition for the Treatment of Basal Cell Carcinoma. Targ Oncol 14, 253–267 (2019). https://doi.org/10.1007/s11523-019-00648-2

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