RESUMO
Vismodegib (Erivedge, Genentech-Roche) is the first in class of Hedgehog pathway inhibitors approved for treatment of metastatic basal cell carcinoma (BCC), or locally advanced BCC that has recurred after surgery or is not amenable to surgery or radiation. Its path to discovery has been unique and traces its origin to corn lilies, sheep, Drosophila flies, and the Hedgehog signaling pathway. J Drugs Dermatol. 2018;17(5):506-508.
Assuntos
Anilidas/história , Antineoplásicos/história , Piridinas/história , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/secundário , História do Século XX , História do Século XXI , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/secundário , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Estados UnidosRESUMO
INTRODUCTION: Vismodegib is the first Hedgehog (Hh) pathway inhibitor approved in the US for the treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC). It was approved by the US FDA on 30 January 2012, and by the European Commission on 12 July 2013, for the treatment of adult patients with symptomatic metastatic BCC, or locally advanced BCC inappropriate for surgery or radiotherapy. Vismodegib selectively inhibits the Hh signaling pathway, binding to and inhibiting a critical signal-transducing component of the pathway, Smoothened (SMO). Vismodegib was discovered by Genentech, Inc., under a collaboration agreement with Curis, Inc. AREAS COVERED: This article reviews the development of vismodegib from its discovery, preclinical pharmacology and validation to the clinical pharmacokinetics and validation in Phase I and II clinical investigations. We also provide a survey of other Hh pathway inhibitors in clinical development. EXPERT OPINION: The authors' experience in target-based drug discovery suggests that vismodegib's path to the clinic deserves some reflection to identify key steps that have contributed to its success. Targeting the Hh pathway with vismodegib blocks the abberant signaling caused by mutational inactivation of the negative regulator PTCH1 or mutational activation of SMO. Vismodegib gives physicians a treatment option for patients with locally advanced or metastatic BCC for whom surgery or radiation is not recommended.
