New Hopkins-tested cancer treatment strikes at source

A new type of anti-cancer drug, one that interferes with cancer cells on a molecular level, has shown promising results for patients with advanced stages of skin and brain cancer.

Results from initial trials of the drug, developed by biotech company Genentech and called GDC-0449, were published in two papers in the New England Journal of Medicine earlier this month. Hopkins Hospital is one of three hospitals where the drug trials have been taking place for the past 10 months.

Doctors gave the drug to 33 patients with locally advanced or metastatic basal-cell carcinoma - the most common type of skin cancer. Eighteen patients responded positively to the drug with comparatively few side effects. Eleven other patients had tumors that neither shrunk nor progressed, four patients saw their disease progress, and one patient dropped out of the study.

The drug was also given to a patient with advanced medulloblastoma, a type of malignant brain tumor. His cancer had recurred after a previous treatment, and at the start of the trial, he was bed-ridden and in significant pain.

But within weeks after starting the drug, he had gained weight and was even able to exercise. Positron emission tomography (PET) scans of the patient showed a body almost honeycombed with tumors at the trial's beginning. Two months later, all but a handful had shrunk or cleared. GDC-0449 targets the hedgehog signaling pathway, which is hyperactive in both basal-cell carcinoma and medulloblastoma.

In cancerous cells, a ligand, or small signaling protein, called hedgehog binds to a protein called patched on the surface of the cell. Patched is normally responsible for inhibiting another protein called smoothen. When hedgehog is bound to patched, smoothen is activated and eventually sends a signal to the nucleus that signals the cell to proliferate unnaturally, forming the tumors associated with the disease.

The hedgehog pathway is important during development, but is permanently turned off during adulthood unless mutations disrupt patched's ability to inhibit smoothen, or smoothen's ability to prevent out-of-control cell division.

In other words, in a normal adult cell, hedgehog does not bind to patched, preventing smoothed from becoming activated and giving the go-ahead for cell division. Non-cancerous cells stop dividing when they come into contact with the surrounding cells, but cancerous ones just keep growing.

The GDC-0449 drug works by blocking the pathway that the hedgehog protein initiates and turning off unchecked cell proliferation.

"This is the first time that a molecular pathway fundamental to the development of medulloblastoma has been targeted, and the first time targeting has been shown to be effective," said John Laterra, professor of Neurology, Oncology and Neuroscience at the Hopkins School of Medicine, who participated in the medulloblastoma study.

Existing therapies for medulloblastoma and advanced basal-cell carcinoma often kill healthy and cancerous cells alike, causing painful side effects. Medulloblastoma is currently treated with surgery, radiation therapy and chemotherapy. Advanced basal-cell carcinoma has no known effective chemotherapy treatments.

In contrast, GDC-0449 can specifically target cancerous cells, because such cells are the only ones with an active hedgehog signaling pathway.

"Radiation and chemotherapy are difficult and can lead to toxicity," Laterra said. "One potential advantage of this agent is that it will not have similar toxicity. The other therapies target any tissues growing in an uncontrolled fashion."

However, the patient with the brain tumor, whose tumors had almost all cleared, developed resistance to the drug two months after treatment began, and died shortly thereafter.

Laterra suspects that this patient harbored some cancer cells that had spontaneously mutated to be resistant and grow uncontrollably through mechanisms other than the hedgehog pathway even before he began the trial, just as some bacteria are antibiotic-resistant. During the trial, the drug killed the other, non-resistant cells, but the resistant cancer cells were left free to proliferate.

These case studies show that the drug can still be tweaked to be even more effective, but remains an extremely promising, safer new therapy for patients in advanced stages of these types of cancers.