Emerging drugs and combination strategies for basal cell carcinoma

Expert Opin Emerg Drugs. 2014 Sep;19(3):353-65. doi: 10.1517/14728214.2014.914171. Epub 2014 Apr 29.

Abstract

Introduction: Basal cell carcinoma (BCC) is a malignancy that is driven by an activated Hedgehog (Hh) pathway. Smoothened inhibitors are a new promising treatment option for patients with locally advanced or metastatic BCC or basal cell nevus syndrome. But long-term data are still limited, the optimal treatment duration is not yet defined and there are already documented cases with acquired resistance.

Areas covered: Treatment modalities with Hh inhibitors, side effects and potential pharmacological combination options are discussed. The current literature, including PubMed, Cochrane database and registered trials on ClinicalTrials.gov, was searched.

Expert opinion: BCCs typically regress during therapy with Hh inhibitors. Muscle toxicity, dysgeusia and hair loss can be considered as on target adverse reactions. Muscle toxicity is the dose-limiting toxicity of sonidegib. It was not seen with vismodegib because of its high binding to plasma protein α-1-acid glycoprotein. Sonidegib is different and shows a clear dose-toxicity relationship, which allows to address the question of whether there is a dose dependency of regression rate, cure rate and progression-free survival. In addition, basic research has offered strategies to enhance efficacy by the combination with other molecules, such as EGFR inhibitors, MEK inhibitors or immunotherapy.

Keywords: Hedgehog inhibitors; adverse events; basal cell carcinoma; combination therapy; resistance; side effects; smoothened inhibitors; sonidegib; toxic myopathy.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Basal Cell / drug therapy*
  • Carcinoma, Basal Cell / pathology
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Drug Design
  • Hedgehog Proteins / antagonists & inhibitors
  • Humans
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology
  • Smoothened Receptor

Substances

  • Antineoplastic Agents
  • Hedgehog Proteins
  • Receptors, G-Protein-Coupled
  • SMO protein, human
  • Smoothened Receptor