Julie Breneiser and her son have an inherited condition called basal cell nevus syndrome.
At times in her life, Julie Breneiser has simply stopped looking in the mirror. She didn't want to see the lesions on her skin or the scars from her many surgeries. Two years ago, the 53-year-old Breneiser underwent surgery to remove lesions every month for 6 months. “With each procedure, I missed work and had to explain my appearance to people,” she recalled.
Breneiser and her two teenage children, who live in eastern Pennsylvania, have basal cell nevus syndrome (BCNS), a rare condition that predisposes them to develop lesions called basal cell carcinomas (BCCs). Some people with this inherited syndrome develop hundreds or thousands of BCCs and may experience other health problems.
Until recently, surgery has been the only treatment. But last year Breneiser enrolled in a clinical trial testing an experimental drug, a pill called GDC-0449. The drug interrupts cancer-promoting messages from the hedgehog signaling pathway, which is switched on inappropriately in individuals with the genetic mutation that causes the inherited syndrome.
For Breneiser, the treatment has brought dramatic results. “This has changed my life,” she said. “To be involved in this trial—that may, some day, so positively change the lives of my children and thousands of others with this syndrome—is completely empowering and overwhelming.”
Since starting the drug in January 2010, 60 percent of the BCCs that she had at the start of the trial have disappeared. Shallow pits on her palms, which are common among many people with BCNS, are also gone.
Others participating in the trial, which included 41 people, have had similar responses. Last December, the committee monitoring the trial concluded that there was a clear benefit from the drug and cut short the randomization part of the trial.
“Stunning” Preliminary Results
Dr. Ervin Epstein, Jr., of the Children’s Hospital Oakland Research Institute presented preliminary results from the study of GDC-0449 at the opening plenary session of the AACR annual meeting on April 3. The treatment prevented the development of new tumors and shrank existing ones, markedly reducing the number of lesions that were big enough to warrant surgical attention, he said.
“This drug replaces the function of the missing gene, and it actually works,” said Dr. Epstein, who has been studying the disease for 25 years. “The tumors basically melt away.”
These are “stunning” results, said Dr. Daniel Von Hoff of the Translational Genomics Research Institute at the plenary. At the 2009 AACR annual meeting, Dr. Von Hoff presented positive results from the first trial of GDC-0449 in people with advanced BCC.
Based on his experience treating the disease, he stressed that the syndrome can be miserable for people. Some will be reclusive, choosing not to go out in public. The new drug represents a “breakthrough with a capital B,” he added.
Side effects from the drug include hair loss, loss of the ability to taste, and muscle cramps. Some patients have chosen to stop taking the drug after a year or less because of these side effects. When the drug was stopped, some of the lesions returned.
“We're not there yet, but this is a wonderful milepost of progress,” said Dr. Epstein. His collaborators included Dr. David Bickers of Columbia University Medical Center, who saw Julie Breneiser and about half the patients in the trial.
Fundamental Knowledge, Clinical Possibilities
Future studies will experiment with different doses and schedules of the drug to see if the same benefit can be achieved with fewer side effects, noted Dr. Jean Tang of the Stanford University School of Medicine and the first author of the study.
For years, no company wanted to invest in developing a targeted therapy for a rare disease that could be treated with surgery. Then, in 2004, researchers linked the hedgehog pathway to some common cancers, and almost overnight many companies began to develop inhibitors. At least two dozen clinical trials are now testing these agents. Developed by Genentech, GDC-0449, also called Vismodegib, is the farthest along.
Dr. Epstein co-led one of two research teams that identified the genetic mutation underlying BCNS in 1996, after a decade-long search. Years of research on the hedgehog pathway in model organisms provided the basic knowledge needed to move ahead with developing potential therapies.
“This story is a wonderful example of a clinical benefit based on fundamental molecular knowledge,” said Dr. Epstein. “Who would have thought that trying to identify the gene in this very rare disease would eventually lead to clinical trials for common cancers?”
Dr. Von Hoff credited “some extraordinary observations and drug development” with making the current study possible, but he said that clinical science was important, too. “[The researchers] had to find the patients who would have the best chance of benefiting from the new agent,” he noted.
In patients with a strong genetic predisposition to develop BCCs, the drug’s preventive effects were evident within a year. “This study suggests a new way of doing prevention research that focuses on individuals who have a high tumor burden or genetic predisposition,” said Dr. Tang.
“We get a lot of help from a support group,” she added. The Basal Cell Carcinoma Nevus Syndrome Life Support Network, which includes more than 575 families, each with several affected members, provides information about the disease and helped with the recruitment for the trial.
“Our message is that you are not alone,” said Kristi Burr, the network's executive director. The network supports participants in the trial and, through social media tools like Facebook and Twitter, connects people living in remote areas and those who may be reclusive.
“We say to people that you have to live your life every day,” said Burr. “You can’t be held hostage by this condition, and this therapy is removing the shackles.”
For Julie Breneiser, the therapy has made the scars from her many previous procedures smoother and less prominent. Without having to undergo regular surgeries, she has more time for her family and her work helping children who have disabilities. “And I even like what I see in the mirror!” she said.
—Edward R. Winstead
Further reading: In Cancer, Hitting a Target Called Hedgehog ► NCI Cancer Bulletin for September 8, 2009 - National Cancer Institute
NCI Cancer Bulletin for April 5, 2011 - National Cancer Institute
Biography - Edward Winstead
Edward “Ted” Winstead has written about genes and genomes for more than a decade. He joined the NCI Cancer Bulletin in 2005 after being a reporter for the Genome News Network, where he was introduced to many of the genomic tools now used to study cancer. A graduate of the master’s program in science writing at Johns Hopkins University, Ted stays up to date on the latest developments in cancer research and genomics with help from the scientists and writers he follows on Twitter. You can follow his tweets from @NCIBulletin and @EdwardWinstead.
Selected articles by Ted Winstead:
Biography - Edward Winstead - National Cancer Institute
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