Behind cancer drug, a 30-year history of scientific breakthroughs

Norbert von der Groeben

Dermatologist Jean Tang chats with Winnie Bazurto, who benefited from a drug recently approved for the treatment of inoperable basal cell carcinoma. The cancer had formed on Bazurto's lower right eyelid.

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.

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 didn't look good. Although 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 the television set.

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 the story behind 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.

Considered a landmark in cancer treatment, it's hoped there will be many more hedgehog-inhibiting drugs to come for the treatment of other invasive cancers — not just inoperable basal cell carcinomas like Bazurto's, but pancreatic, esophageal and ovarian cancers as well.

"That's the exciting part about this drug," said Anthony Oro, MD, PhD, a professor of dermatology at Stanford who was part of the original hedgehog cancer studies, and involved in the study that led to the approval of the drug, nicknamed vismo. "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 vismo pills offered to Bazurto by her Stanford dermatologist Jean Tang, MD, PhD, assistant professor of dermatology — one of the many scientists at Stanford and around the world involved in research that led to the drug's development.

For Bazurto, the new drug sounded like a good option. She agreed to give the pills a try.

The story behind the development of vismo is a 30-year history of scientific breakthroughs, one building upon the next, as they emerged from the laboratories of biologists who were working to understand how genetic pathways affect the development of life.

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.

Scientists wanted to understand the mystery of embryogenesis.

It was the result of fruit fly studies by scientists Christiane Nüsslein-Volhard, Edward Lewis and Eric Wieschaus that eventually provided the answer — winning them the Nobel Prize. In their studies of thousands of newly created mutant fruit fly strains, the scientists identified 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. (They named it hedgehog because, when mutated, the gene caused the flies to grow a coat of spines all over their undersides.) Remarkably, other researchers identified a similar gene in humans and other vertebrates, indicating that the gene had been present in common ancestors more than half a billion years ago.

Norbert von der Groeben

Matthew Scott, a key player in the history of hedgehog gene research, noted that the cancer drug based on that research was approved by the FDA on his birthday. "To see the culmination of 30 years of research help patients live their lives better is enormously gratifying," he said.

These major discoveries excited the scientific community, triggering 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, professor of developmental biology at Stanford.

"Scientists wanted to discover how all the molecular switches, gears, pipes, transport systems — all sorts of machinery — worked to control the organization of embryos during their development. The hardware — genes and proteins like hedgehog — is deployed somewhat differently in different animals, like species-specific software, to give rise to the vast diversity of animal forms," Scott said.

Sixteen years after the fruit fly discoveries, in 1996, Scott and a team at UC-San Francisco led by Ervin Epstein Jr., MD, professor of dermatology, made another huge discovery that would connect 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.
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Sixteen years later, in April 2012, Bazurto, who lives in San Mateo, Calif., started taking the daily vismo pills with the hope of saving the sight in her right eye.

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 non-melanoma skin cancer that looked like an small open wound on her arm.

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

"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 post-surgical visit with Tang, her dermatologist, her hair was thinning, but her eye looked great.

"Oh you look so gorgeous!" said Tang when she walked into the examination room and first saw Bazurto seated in her wheelchair at the Stanford Medicine Outpatient Center in Redwood City. Bazurto was joined by her daughter and granddaughter all crowded into the small room.

Bazurto rolled her eyes and laughed. She was wearing a floral dress with pearl earrings. Tang was dressed in a white lab coat. When they first met in April, Tang was very pregnant and Bazurto was losing her sight. Now Tang had a healthy baby boy, and Bazurto could see clearly out of her right eye.

"I can't seem to find a good wigmaker," Bazurto said. "They don't think I'll live long enough to pay for it," she joked.

Tang ran her hands gently through Bazurto's thin, white hair. (In another month, it would all fall out, but her doctor promised it would grow back.) Then Tang gently tapped the skin next to her patient's eye, 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 Stanford labs.The hope is that their work will help lead to more new drugs, more quickly, Oro said.

"When vismo was approved, my son said, 'Dad, that was cool. Is it going to take you that long to find the next one?'" Oro said, laughing.

Both Oro and Tang were involved in the first clinical trials testing vismodegib on basal cell carcinoma tumors.

"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."

For many of the basic scientists involved in this research, the clinical use of hedgehog-inhibiting drugs to treat patients like Bazurto — while not the original goal of their research — is the ultimate success.

"The FDA approval came out on my birthday, Jan. 30," Scott said. "I can't imagine a better birthday present. Even though I had nothing directly to do with vismodegib, to see the culmination of 30 years of research help patients live their lives better is enormously gratifying — and a testimony to basic science."

Bazurto, a small woman in a wheelchair who loves baseball and football and has been known to occasionally wager on the 49ers, is today considered somewhat of a rock star among hedgehog scientists in part because of her great response to the hedgehog-inhibiting drug and in part because of her advanced age. The surgeon, her doctor and her nurses all crowded into the small examination room to take photos with her for her post-op visit in October. She smiled widely and mentioned that a Genentech scientist also brought her flowers.

"He's the vice president of research at Genentech (Fredric de Sauvage) who has been studying the hedgehog pathway for 20 years," Tang said. "I sent him your picture. He said it almost made him cry. I'm sure it was the crowning moment of his career."