Sunday, December 23, 2012


Original Article

Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma

Daniel D. Von Hoff, M.D., Patricia M. LoRusso, D.O., Charles M. Rudin, M.D., Ph.D., Josina C. Reddy, M.D., Ph.D., Robert L. Yauch, Ph.D., Raoul Tibes, M.D., Glen J. Weiss, M.D., Mitesh J. Borad, M.D., Christine L. Hann, M.D., Ph.D., Julie R. Brahmer, M.D., Howard M. Mackey, Ph.D., Bertram L. Lum, Pharm.D., Walter C. Darbonne, M.S., James C. Marsters, Jr., Ph.D., Frederic J. de Sauvage, Ph.D., and Jennifer A. Low, M.D., Ph.D.
N Engl J Med 2009; 361:1164-1172September 17, 2009DOI: 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.)
Figure 1Mechanism of Action of GDC-0449 and Response to Treatment.
Figure 2GDC-0449 Activity in Patients with Locally Advanced Basal-Cell Carcinoma.

Article Activity

238 articles have cited this article
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This article point to the importance that targets of therapy should not only focus on steps within the main pathways but also on regulator of speed of reaction.  Basal  Cell cancer generally do not metastasize but once the speed of reaction is increased or promoted, the disease becomes more aggressive.  The Hedgehog genes promotes this disease and have been recently targeted effectively to show response to therapy.

Metabolic reaction can be promoted by a promoter gene in the main DNA, or by a variety of transcription genes which ultimately lead to a set of enzymes which ultimately accelerate the reaction.

It is also important to try to pay attention to Gradiants of Morphogens which apparently   govern cellular differentiation based of cell position in the body.  Controlling such determination may prove a way to impose changes within cancer cells!

It is of interest that in Breast cancer, basaloid type, the stage of disease had been reported to be "late" or advanced at diagnosis. This fact in combination with a triple negative status of this cancer lead to a poor prognosis.  Is Reducing the speed of reaction a critical component of future treatment in this disease? This type of Breast cancer is genetically similar to Ovarian cancer, therefore it fair to conclude that Target therapy successes in basal cell like breast cancer could be replicated in Ovarian cancer and vice-versa?


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