When his mother was diagnosed with glioblastoma 20 years ago, Dr. Barry Stoddard knew the trajectory she’d almost certainly face in the months ahead.
Stoddard, a protein engineer at Fred Hutchinson Cancer Research Center, had very recently seen that path in a friend and colleague — Dr. Harold Weintraub, one of the founders of the Hutch’s Basic Sciences Division, where Stoddard leads his laboratory team. Weintraub died of the same rare but aggressive brain cancer exactly a year before his mother’s diagnosis.
Judy Stoddard was a warm and loving mother and grandmother, a well-respected but tough school teacher, and she cooked a mean chicken cacciatore, her son said. She was upbeat about her disease and sure she’d beat it, but she lived only 14 months past her diagnosis. She died in 1997, at 59 years old, on her 38th wedding anniversary.
Stoddard, an expert in capturing proteins’ 3-D forms and engineering them for different potential therapeutic purposes, got involved in a research project a few years later to modify a protein from yeast for possible use as part of a targeted cancer therapy. The modified protein was the brainchild of Washington State University biologist Dr. Margaret Black, who recognized that with a few tweaks this natural molecule could have potent anti-tumor power.
The research team published a paper describing the engineered enzyme in 2005 and showed that the protein showed promise against tumors in an animal model in 2008, and Stoddard moved on to other projects.
But several years later, he was delighted to learn from Black that their work was being tested as part of a small clinical trial for patients with aggressive glioblastoma, led by a biotech company in San Diego, Tocagen.
Last month, the company researchers and their colleagues reported results from that early-stage trial in the journal Science Translational Medicine. The enzyme — and the rest of the drug built around it — is safe. And it may be extending patients’ lives.
“It’s every basic scientist’s dream to see something that they do, that’s entirely curiosity-driven to start with, actually turn into something useful,” Stoddard said. “And to suddenly realize that there are people walking around, getting to spend more time with their families, who otherwise would be dead, because they have an enzyme inside of them that was created in your lab — that’s a pretty amazing feeling.”
When asked if he thought about his mom, Weintraub and other friends taken by brain cancer when he heard about the trial, Stoddard didn’t hesitate.
“Of course. Those people all meant a lot to me,” he said. “I’m sure they’d be really thrilled to know how things have been going.”
The strategy Black proposed to Stoddard, like many therapies, was based on a set of molecules that exist in nature. The simple, single-celled yeast — that of beer- and bread-making fame — makes a certain kind of protein that more complicated creatures (like humans) don’t possess, Stoddard said.
The yeast uses this enzyme — a type of protein that spurs an active change in the cell — to quickly switch the building blocks of DNA from one type of block to another. Humans are less efficient — we have to do our DNA construction from the ground up.
It turns out that enzyme can also switch another molecule — 5-fluorocytosine, or 5-FC, a very safe drug used to treat fungal infections — to a related molecule called 5-fluorouracil, or 5-FU, a potent chemotherapy drug that is already FDA-approved and in clinical use for many cancers. This technique falls into a class of therapies known as pro-drugs, which use a combination of a harmless drug precursor and another molecule (like the yeast enzyme) that catalyzes them in the body to turn into an active drug.
“This ends up being an extremely powerful enzyme-pro-drug combination,” Stoddard said.
Stoddard and his team first captured the 3-D structure, atom by atom, of the yeast enzyme then re-engineered it to be more stable and to keep its shape at human body temperature.
The pro-drug strategy is coupled with what is known as a “suicide gene,” a form of gene therapy that delivers DNA bearing instructions coding for the enzyme selectively to cancer cells. The brain cancer-targeting drug built by Tocagen researchers, known as Toca 511, uses a special kind of virus to ferry the engineered enzyme gene to tumor cells. The virus only infects actively dividing cells — of which there are very few in the brain, other than cancerous cells. It’s also normally cleared by an active immune system, but tumors often suppress surrounding immune cells to evade detection — meaning the virus can remain in the brain in the area near the tumor.
The virus bearing a gene coding for the engineered yeast enzyme is injected into the tumor area of the brain during a patient’s surgery to remove the tumor — brain tumors, especially glioblastoma, are notoriously difficult to remove completely by surgery. The virus should, in theory, spread only to replicating tumor cells, bringing the enzyme gene along with it. Patients then take a harmless tablet of 5-FC, which the body will convert to the 5-FU chemo drug in cells bearing the engineered enzyme — i.e., the tumor cells.
The study, which was a Phase 1 clinical trial designed primarily to test the treatment’s safety, looked at Toca 511 in 43 patients with recurrent glioblastoma (or another aggressive brain cancer known as astrocytoma) from seven different sites around the U.S. Typically, patients with these cancers whose tumors have come back after treatment survive an average of just eight months, said Dr. Asha Das, a neuro-oncologist who heads clinical development at Tocagen and was one of the study authors. By comparison, the 43 patients in their study survived an average of nearly 14 months, she said.
It may not seem like a huge change, but for a disease with few alternatives when the standard treatments (surgery, radiation and chemotherapy) fail to work, it’s a step in the right direction. And there’s a hint that the therapies might work even better for a subset of the brain cancer patients, Das said. About 40 percent of the patients in the small trial were still alive two years past the start of the trial — compared to less than 10 percent for patients who received the standard treatment. (As all the patients in the Toca 511 trial received the drug, the researchers compared them to a control group of patients from a previous, larger clinical trial.)
Although the primary goal was to ensure the drug’s safety, “we were enormously excited to see this type of change,” said Das, who used to head the neuro-oncology program at Cedars-Sinai Medical Center in Los Angeles. “These patients have very few treatment options.”
The study looks like an interesting approach, said Fred Hutch neurobiologist Dr. Eric Holland, who specializes in glioblastoma. But it’s important to remember that Phase 1 studies are only designed to test the approach’s safety, Holland said, and larger studies are needed before a drug’s efficacy can be truly proven.
“The output of a Phase 1 trial, the metric of passing that trial, is safety,” Holland said. “You really don’t know about efficacy until you get to the Phase 2, where you’re powered to really know.”
Holland also pointed out that other research groups are also pursuing virus-based therapies for glioblastoma and, so far, they are all still in similarly early phases or have failed to pan out in larger studies. Tocagen is currently enrolling patients for a larger, Phase 2/3 study, Das said, that will compare the experimental drug to the standard of care in a total of 170 patients.
For now, Stoddard is thrilled by the path his engineered enzyme is on. His work — like that of many basic scientists — is fostered both by a sense of curiosity and an eye toward future applications of the research.
“Basic scientists can have a real role in fostering translation,” he said. “Sometimes, the most important types of tools for eventual clinical treatment come out of the most unexpected places.”
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.