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.
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.)
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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