Hedgehog Signaling Inhibitor
Genentech (www.gene.com) currently has a drug in the clinic that inhibits Hedgehog signaling in neoplastic cells. Developed in collaboration with Curis (www.curis.com), GDC-0449 is an orally bioavailable small molecule that antagonizes the Smoothened receptor involved in the Hedgehog signaling pathway.
GDC-0449 is a derivate of cyclopamine, a natural compound found in wild corn lily. Cyclopamine is a teratogen and its discovery was based on the observation that pregnant ewes grazing on the wild corn lily produced cyclopic offspring.
Last year at the AACR meeting, researchers from Johns Hopkins presented data revealing that cyclopamine inhibited glioblastoma multiforme growth by antagonizing the Smoothened receptor. The investigators found that malignant cells treated with cyclopamine downregulated the expression of Gli1—a nuclear protein whose presence is associated with Hedgehog signaling.
Hedgehog signaling is a key regulator of both insect and animal development. In mammals, the pathway is involved in regulating the fate of progenitor cells. Many cancer researchers believe that aberrant Hedgehog signaling can give rise to a malignant population of cancer stem cells.
The pathway involves two receptors, Patched and Smoothened. When the Patched receptor is not bound to its sonic Hedgehog ligand, it prevents the expression and activity of Smoothened. A majority of aberrant Hedgehog signaling in cancer cells is a result of a mutation in the Patched receptor (90%). A mutated Patched receptor results in Smoothened being in an activated state, which causes constant Hedgehog signaling and, thus, the hyperproliferative state of malignant cells.
James C. Marsters, Ph.D., a scientist at Genentech, noted in his presentation that GDC-0449 was found to be 10 times more potent than cylopamine in antagonizing Smoothened’s activity.
Daniel D. Von Hoff, M.D., from TGen (www.tgen.com), presented preliminary Phase I results involving GDC-0449 for the treatment of nine patients with locally advanced or metastatic basal cell carcinoma. In a dose-escalation open-label study, the patients were administered various doses of the drug (either 150, 270, or 540 mg/day) once a day. Dr. Von Hoff noted that over a long duration of therapy, there were mild toxicities associated with the drug (loss of hair and weight loss), but it was generally well tolerated.
One of the nine patients had tumor progression and died, while the remaining eight patients demonstrated tumor regression and remained in the study for 128–148 days. Tissue biopsies from patients revealed a downregulation of Gli1 expression, which demonstrated that the drug was having an effect on blocking Hedgehog signaling concomitant with tumor regression.
Interestingly, although there were over one million cases of metastatic basal cell carcinoma reported in the U.S. in 2008, it is still classified as a rare disease. Ninety percent of the metastatic disease has a Patched mutation, which most likely gives rise to cancer stem cells. If Genentech is able to obtain orphan drug approval from the FDA, GDC-0449 may have the potential to become a blockbuster drug as a first-line therapy for treating cancers.