Special Report

In Cancer, Hitting a Target Called Hedgehog

Positron-emission tomographic (PET) scans of a man with medulloblastoma treated with GDC-0449. Scan A (left) shows the patient prior to treatment. Scan B (middle) shows dramatic tumor shrinkage after 2 months on the drug, but a month later the cancer had progressed (scan C, right). (Images courtesy of The New England Journal of Medicine ©2009) [Enlarge]

When new cancer drugs are first tested in people the main goal is to see whether an agent is safe and shows promise. Dramatic responses from patients are rare. So when a closely watched clinical trial published last week showed that patients with untreatable skin cancers had benefited from an experimental drug, it was good news for patients and researchers alike.

The trial was testing a drug designed to block the hedgehog signaling pathway, a cascade of interactions in cells that is essential as embryos develop. The pathway tends to be silent in most adult tissues, but it is switched on improperly in some cancers. A number of companies have experimental hedgehog inhibitors aimed at shutting down this important pathway when it is activated at the wrong time.

Mutations that turn on the pathway are common in basal cell skin cancer, and the trial included 33 patients with very rare cases of the disease, in which the cancer had spread or become so invasive that surgery was no longer an option. Among this group, however, half of the patients responded, some in dramatic fashion.

“This response was great to see, because in most phase I clinical trials you are simply trying to get the dose right and see how the drug behaves in the body,” said lead investigator Dr. Daniel Von Hoff of the Translational Genomics Research Institute (TGen). “This was something really special, and we’re hoping to see more of it.”

Some tumors began to shrink just weeks after patients started taking the drug and side effects were manageable, the researchers reported last week in the New England Journal of Medicine (NEJM). Although the drug—a pill known as GDC-0449—stopped working in some patients, others took it for upwards of 20 months, said coauthor Dr. Charles M. Rudin of the Johns Hopkins Kimmel Cancer Center.

New Options

“What makes this study particularly exciting is that we really have had little to offer patients with advanced basal cell carcinomas,” Dr. Rudin continued. “We now have a well-tolerated drug that can induce clinical responses in patients with a fairly high frequency.”

In addition to Johns Hopkins and TGen, patients were treated at the Wayne State University Karmanos Cancer Institute in Detroit. The study was sponsored by Genentech, which makes the drug, and the company has opened a phase II trial for patients with this rare type of advanced skin cancer.

The drug is also being tested in children and in young adults with a brain tumor called medulloblastoma. A second report in NEJM describes the experience of a 26-year-old man with metastatic medulloblastoma who had a remarkable but transient clinical response to GDC-0449. Within weeks of starting the drug, he went from being bedridden and in considerable pain to being able to exercise and having no pain. Unfortunately, the disease eventually progressed, and the man died.

“The initial scans looked wonderful, with a really dramatic improvement in the extent of his disease, but his improvement was quite transient,” said Dr. Rudin. “Certainly, most of the responses in the basal cell carcinoma appear to be more durable.”

Dr. Andrzej Dlugosz of the University of Michigan Comprehensive Cancer Center, who coauthored an editorial accompanying the reports, called the results “quite exciting.” He said that the two reports demonstrate the promise of this new class of cancer treatments.

The results need to be confirmed in larger studies, he cautioned, and said it will be important to try to understand why some patients develop resistance to the drug, as often happens with molecularly targeted cancer drugs. (An analysis of the mechanism of drug resistance in the man with medulloblastoma appeared online in Science last week.)

Three Strategies

Dr. Von Hoff presented results on a few patients in the trial at the American Society of Clinical Oncology annual meeting earlier this year, where he said that “the hedgehog pathway is one of the most exciting and promising targets in cancer research.”

He then outlined three ways that hedgehog inhibitors could help treat cancer: by targeting tumors driven by the pathway, improving the delivery of conventional drugs, and providing a way to attack rare populations of cells that may give rise to tumors.

While it is critical in embryonic development, the hedgehog pathway also appears to be active in some types of self-renewing cells (also called cancer stem cells) that some researchers believe are critical for the development of some cancers. Many investigators are exploring the idea of disabling these cells by inhibiting the hedgehog pathway.

Hedgehog inhibitors may also boost conventional cancer drugs by altering the local environment around tumors. In May, British researchers said that a hedgehog inhibitor called IPI-926 helped a chemotherapy drug reach pancreatic tumors in mice when it was given along with chemotherapy. The animals that received the combination treatment fared better than those that did not, the team reported in Science.

“Among the pancreatic cancer research community, there is tremendous interest in hedgehog inhibition and the ability to improve the delivery of drugs to pancreatic tumors and ultimately prolong survival,” said Dr. Margaret Read, who leads the team that developed IPI-926 at Infinity Pharmaceuticals.

“In the scientific community,” she added, “hopes have been high that hedgehog inhibitors would work in basal cell carcinoma, and it’s great to see that one has. The big question now is where else will they work?” Based on preclinical data suggesting the importance of this pathway in many cancers, her group and others are testing hedgehog inhibitors in a variety of tumors.

In addition to basal cell carcinoma and medulloblastoma, Genentech is testing its drug in cancers where the hedgehog pathway may be active but where mutations in the pathway do not appear to be present, such as colon and ovarian cancers, said Dr. Josina Reddy, medical director at the company and co-author of the basal cell carcinoma paper.

Genentech plans eventually to seek approval for GDC-0449 as a treatment for locally advanced and metastatic cases of basal cell skin cancer based on the results of the ongoing trials, she added.

In the meantime, the dramatic responses observed in the current study illustrate the promise of a relatively new approach to developing drugs for cancer, noted Dr. Rudin.

“We’re linking the molecular biology that underlies a disease to the development of targeted therapies, and then testing them in patients who are likely to respond,” he said.

—Edward R. Winstead