Emerging drugs and combination strategies for basal cell carcinoma.
BACKGROUND
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.


METHODS
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.


CONCLUSIONS
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.
University Hospital Zurich, Department of Dermatology , Gloriastrasse 31, CH-8091 Zurich , Switzerland.
Jil
J
Dreier
Reinhard
R
Dummer
Lea
L
Felderer
Mirjam
M
Nägeli
Sharon
S
Gobbi
Rainer
R
Kunstfeld
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000072086:Smoothened Receptor
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor
Hedgehog inhibitors; adverse events; basal cell carcinoma; combination therapy; resistance; side effects; smoothened inhibitors; sonidegib; toxic myopathy