Stanford Medicine Newsletter Updates For the Local Community

 

30 years of science lead to valuable cancer drug

One gene, many researchers, future hope

Stanford dermatologist Jean Tang, MD, PhD, helped develop a drug that saved the eyesight of 101-year-old Winnie Bazurto.

   

Three years ago, 101-year-old Winnie Bazurto noticed a strange growth on her lower eyelid. She didn’t worry about it initially, but in 2012 it started getting bigger, fast—doubling in size every two weeks and growing into the orbit of her right eye, restricting her vision.

It was diagnosed as basal cell carcinoma, the most common skin cancer. Her main concern was that the painful growth would infiltrate the eyeball, possibly causing blindness. Bazurto’s options for treatment did not look good. Although she is still healthy, her age meant she was not a candidate for the eight-hour surgery necessary to remove the growth or the alternative, six weeks of radiation treatment. But she was reluctant to lose the sight in her right eye and, along with it, much of her independence—not to mention her ability to watch a fastball on television.

Then a third option emerged: a new drug approved by the U.S. Food and Drug Administration in January 2012 called vismodegib (brand name Erivedge) to treat inoperable basal cell carcinomas.

Like most patients prescribed a new drug, Bazurto knew little about its origins. The Genentech-developed drug is the first class of drugs approved by the FDA that works by inhibiting one of the key regulators in human development: the hedgehog molecular signaling pathway.

The hedgehog connection

This approach is considered a landmark in cancer treatment, and it’s hoped that there will be many more hedgehog-inhibiting drugs to come for the treatment of other invasive cancers, including pancreatic, esophageal and ovarian cancers.

“That’s the exciting part about this drug,” said Anthony Oro, MD, PhD, professor of dermatology at Stanford, who was part of the original hedgehog cancer studies. “Now, hopefully, we will develop more of these types of drugs for other cancers in a faster cycle time.”

Faster is the key word here, considering that more than 30 years of painstaking scientific research lie behind the development of the little pink-and-gray pills offered to Bazurto by her Stanford dermatologist Jean Tang, MD, PhD, assistant professor of dermatology. Both Oro and Tang were involved in the first clinical trials testing vismodegib on basal cell carcinoma tumors.

The drug’s origins date back to a scientific quest in the 1970s to answer a crucial question of developmental biology. Scientists knew that a developing embryo started out as a ball of identical cells, but nobody yet understood how these cells knew when or where to grow body parts, such as arms and legs.

Rooted in research

Through fruit fly studies scientists were able to identify more than 50 genes needed to control the formation of the embryo, including one they named hedgehog. The hedgehog gene was found to regulate the organization and pattern of fly body parts. Remarkably, other researchers identified a similar gene in humans and other vertebrates, indicating it had been present in common ancestors more than half a billion years ago.

These major discoveries triggered a new round of research to determine exactly how genes control the growth of animals. One of those scientists, who would prove to be a key player in the history of hedgehog research, was Matthew Scott, PhD, Stanford professor of developmental biology.

Sixteen years after the fruit fly discoveries, in 1996, Scott and a team at UC-San Francisco made another huge discovery that connected the hedgehog pathway and certain cancers. They discovered that defects in hedgehog or related genes were present in two cancers: basal cell carcinoma, the most common human cancer, and medulloblastoma, a highly malignant pediatric brain tumor.

“These genes, discovered first in flies, tell the cells of a growing embryo when and where they should divide,” Scott said. “If the system breaks down, cells will divide when they should not, and that’s cancer.”

A new round of research took off. Scientists set out to discover therapies that could treat certain cancers by blocking the hedgehog pathway when it had gone awry.

Sixteen years later, in April 2012, Bazurto, who lives in San Mateo, started taking the drug.

Taking things in stride

Bazurto has seven grandchildren, nine great-grandchildren and two great-great-grandchildren. She’s survived the Depression, the recent recession and three husbands. She took the new treatment for skin cancer, and its potential side effects, in stride. Her appetite dampened a bit; she had some leg cramping. Most disturbing for her was some hair loss. She also developed an undocumented side effect—a squamous cell cancer, another type of skin cancer that looked like a small open wound on her arm.

But within just a few months, the basal cell carcinoma had shrunk significantly.

“All of the lesions pretty much disappeared four months after she started taking the pill,” said her granddaughter Gale Carli, a nurse from San Mateo. “It was amazing.”

In August, Bazurto stopped taking the drug and had surgery to remove the remaining growth on her eye. The surgery took only an hour and a half and required no general anesthesia. A similar surgery was performed on the new growth on her arm, which healed up nicely. When she arrived in October for a postsurgical visit with Tang, her dermatologist, her hair was thinning, but her eye looked great.

“Oh you look so gorgeous!” said Tang when she saw Bazurto seated in her wheelchair at the Stanford Medicine Outpatient Center in Redwood City. Bazurto laughed. When they first met in April, Tang was pregnant and Bazurto was losing her sight. Now Tang had a healthy baby boy, and Bazurto could see clearly out of her right eye.

Tang ran her hands gently through Bazurto’s thin, white hair. Then she tapped the skin next to her patient’s eyelid, the site of the surgery.

“Is your vision OK?”

“Oh, certainly,” Bazurto said.

“It’s a little red at the bottom,” Tang said.

“Oh, leave me alone,” Bazurto said, rolling her eyes.

“She’s been the toughest thing ever,” Tang said, shaking her head with admiration.

Today, there are six or seven labs on the Stanford campus that conduct research in the hedgehog pathway. Tens of millions of National Institutes of Health dollars from 1996 to 2013 have gone into fundamental research support for these labs. The hope is that their work will help lead to more new drugs, more quickly, Oro said.

“If a patient only knew the whole story—how the happenstance of science led to their treatment,” Tang said. “If they could go back to when this molecular pathway was first discovered in fruit flies, they’d be amazed. It’s not until the dots are connected 30 years later that it begins to make sense.”

Adds Scott, “To see the culmination of 30 years of research help patients live their lives better is enormously gratifying—and a testimony to the importance of basic science.”

Stanford Medicine Resources:

Footer Links: