A new drug that inhibits the hedgehog signaling pathway has shown "remarkable" antitumor activity against basal cell carcinoma and medulloblastoma, according to two reports.
The hedgehog signaling pathway regulates cell growth and differentiation during early development but is inactive in healthy adults. However, it appears that mutations in components of the pathway can cause malignant growth in some cases of medulloblastoma, the most common brain cancer in children, and in several cancers in adults, notably basal cell carcinoma.
The hedgehog pathway derived its name from its signaling molecule, a polypeptide ligand called Hedgehog [Hh] because the mutation it caused when it was first discovered in fruit flies produced stubby, hairy-looking larvae resembling hedgehogs.
The new oral agent, GDC-0449, was developed to selectively and potently inhibit hedgehog signaling without producing the adverse effects common with conventional chemotherapy. It appears to have done so in a phase I clinical trial of patients with advanced or metastatic basal cell carcinoma and in a single case study testing it against medulloblastoma refractory to all other treatments. Both studies were supported by Genentech Inc., developer of GDC-0449.
These results indicate that targeting the hedgehog signaling pathway may be a promising avenue for a whole new class of cancer therapies, Dr. Andrzej A. Dlugosz and Dr. Moshe Talpaz of the University of Michigan, Ann Arbor, said in an editorial comment accompanying the two reports.
"Although the total number of patients with advanced or metastatic basal cell carcinoma is small, these studies should ignite renewed interest in testing hedgehog pathway inhibitors in patients with typical basal cell carcinoma" as well as other cancers, they said.
"For patients at especially high risk for multiple basal cell tumors, an effective medical treatment would be a welcome alternative to repeated surgical procedures, which can be especially disfiguring when the tumors occur on the face," Dr. Dlugosz and Dr. Talpaz said (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMe0906092
Alternatively, tumor debulking with the use of hedgehog inhibitors, followed by surgical excision, might prove beneficial in many patients, they added.
In the clinical trial, Dr. Daniel D. Von Hoff of the Translational Genomics Research Institute in Scottsdale, Ariz., and his associates assessed GDC-0449 in 18 patients with metastatic and 15 patients with locally advanced basal cell carcinoma that had been refractory to surgery, radiotherapy, and chemotherapy.
A total of 18 patients showed a clinical response, 11 showed stable disease for up to 10 months, and 4 had disease progression, Dr. Von Hoff and his colleagues reported (N. Engl. J. Med. 2009 [doi: 10.1056/NEJMoa0905360
The overall response rate was 55%. Dr. Dlugosz and Dr. Talpaz termed the 50% response rate among patients with metastatic disease "remarkable."
There were no dose-limiting toxic effects or grade-5 adverse events during the study. One grade-4 event occurred (asymptomatic hyponatremia) and several patients reported a variety of problems that may or may not have been related to treatment, such as fatigue and weight loss. Only one patient discontinued treatment after 8 months, citing abdominal pain, fatigue, weight loss, anorexia, and dysgeusia.
In the case study, Dr. Charles M. Rudin of Johns Hopkins University, Baltimore, and his associates assessed GDC-0449 in a 26-year-old man with a 4-year history of medulloblastoma. The patient had undergone gross total resection of the tumor, craniospinal irradiation, extensive chemotherapy, autologous stem-cell transplantation, and additional systemic treatment with temozolomide and bevacizumab, but nevertheless had widespread skeletal and soft tissue metastases. With no alternative therapies left, he was offered CDC-0449.
Within 1 month, supraclavicular lymphadenopathy resolved, sternal masses regressed, and the patient reported that his intractable pain had resolved. After a few more weeks, more nodules regressed and the patient had returned to a normal level of activity. After a few more weeks, further metastases were markedly diminished or, in the case of a disabling epidural mass at C7, no longer detectable.
After 3 months of treatment, however, there was renewed tumor activity, including new lesions as well as regrowth of old lesions. The patient progressed rapidly, despite a series of subsequent therapies, and died.
"The tumor had a remarkable, although incomplete, and rapid, although transient, response to inhibition of the hedgehog pathway with GDC-0449," Dr. Rudin and his colleagues noted (N. Engl. J. Med. 2009 [doi:10.1056/NEJMoa0902903
"The regression is notable because of the tumor burden and the extent of metastasis in this patient, with substantial soft tissue and bony tissue involvement and clinically significant bone marrow compromise, and underscores the primary role that the hedgehog pathway played in maintaining and driving the growth of this patient's tumor," they added.