Towards targeted therapy for basal cell carcinomas?
Basal-cell carcinoma is the most common skin cancer worldwide. Although most patients present with superficial or nodular basal cell carcinomas than can be easily cured with different treatment modalities (such as standard surgical excision, Mohs surgery, cryotherapy, or electrodessication and curettage) some patients can present with unresecable or even metastatic tumors. Mutations in components of the hedgehog signalling pathway have been demonstrated in basal cell carcionoma. In fact, both mutations in two components of this pathway, the PTCH1 tumor-suppressor gene and the SMO gene have been demonstrated both in basal-cell nevus syndrome, and sporadic basal-cell carcinomas.
In a recent report published in the September 2nd issue of The New England Journal of Medicine, a group of investigators from the United States describe their work using GDC-0449, an oral medication that blocks selectively hedgehog signaling by binding to SMO. They treated 33 patients with locally advanced or metastatic basal-cell carcinoma and found an overall response rate was 55%, with a 50% response rate in 18 patients with metastatic disease. There were very few side effects form the medication. Although most basal-cell carcinomas can be cured with different therapies, this new medication offers the possibility to use a target directed therapy for patients with high-risk basal-cell carcinomas, those with aggresive disfiguring tumors on the face, or even to use it as a tumor debulking therapy previous to surgery.
Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma
Daniel D. Von Hoff DD et al
10.1056/NEJMoa0905360
Background
Mutations in hedgehog pathway genes, primarily genes encoding patched homologue 1 (PTCH1) and smoothened homologue (SMO), occur in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and responses of metastatic or locally advanced basal-cell carcinoma to the drug.
Methods
We selected 33 patients with metastatic or locally advanced basal-cell carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day. We assessed tumor responses with the use of Response Evaluation Criteria in Solid Tumors (RECIST), physical examination, or both. Molecular aspects of the tumors were examined.
Results
The median duration of the study treatment was 9.8 months. Of the 33 patients, 18 had an objective response to GDC-0449, according to assessment on imaging (7 patients), physical examination (10 patients), or both (1 patient). Of the patients who had a response, 2 had a complete response and 16 had a partial response. The other 15 patients had either stable disease (11 patients) or progressive disease (4 patients). Eight grade 3 adverse events that were deemed to be possibly related to the study drug were reported in six patients, including four with fatigue, two with hyponatremia, one with muscle spasm, and one with atrial fibrillation. One grade 4 event, asymptomatic hyponatremia, was judged to be unrelated to GDC-0449. One patient withdrew from the study because of adverse events. We found evidence of hedgehog signaling in tumors that responded to the treatment.
Conclusions
GDC-0449, an orally active small molecule that targets the hedgehog pathway, appears to have antitumor activity in locally advanced or metastatic basal-cell carcinoma.
(ClinicalTrials.gov number, NCT00607724.)
