What if cures for some of the worst childhood cancers already existed…and nobody knew it?
In fact, researchers at St. Jude Children’s Research Hospital are betting those cures are out there—hidden among the legions of medicines already used to treat adult cancers and other diseases.
“There is a mistaken belief that all of these drugs have been tried for pediatric cancers. The reality is, they haven’t,” says Anang Shelat, PhD, who plays a central role in drug discovery in the department of Chemical Biology and Therapeutics (CBT). “We say, ‘Let’s test everything we can get our hands on.’ That leads to unexpected discoveries.”
Recently, one of these discoveries has given new hope for children with an aggressive form of medulloblastoma, the most common malignant childhood brain tumor.
The story begins in a laboratory, as it often does at St. Jude. After years of research, Martine Roussel, PhD, of Tumor Cell Biology, and her scientific team had perfected a difficult art: producing medulloblastoma tumors in the lab that accurately mimic human disease. With this valuable resource in hand, they set out to find new ways of destroying those tumors.
“Our focus was to identify drugs that we could move quickly from the laboratory to the clinic, because new treatments are desperately needed for high-risk medulloblastoma patients,” Roussel says.
So, they called a few chemists. And a robot.
Shelat and his colleagues were ready for the call. They used a high-tech robotic system to rapidly test thousands of chemicals for their ability to kill lab-grown tumor cells.
Among the battery of chemicals was a library of more than 1,300 existing medicines. This St. Jude collection, one of the best in the world, includes virtually every drug approved for clinical use in the U.S. to treat any disease.
That’s where the scientists uncovered their prize. After careful analysis, two existing medicines stood out, proving especially potent against the tumors when used together. The pair worked even better when combined with existing chemotherapies against medulloblastoma.
The two drugs, gemcitabine and pemetrexed, are commonly used to fight breast cancer and other aggressive adult tumors. But they had never been tested against medulloblastoma. Without St. Jude, they might have remained hidden in plain sight forever.
The process of finding new uses for existing drugs, known as repurposing, has a major advantage: It is much faster than developing a new drug from scratch. Because gemcitabine and pemetrexed have already met strict U.S. government safety standards for clinical use, St. Jude patients may begin receiving them immediately.
Children and teens with high-risk medulloblastoma are now being treated with the drug pair as part of a St. Jude clinical trial.
Amar Gajjar, MD, co-chair of Oncology, leads that trial, called SJMB12. He hopes the drug pair will improve the outlook for high-risk medulloblastoma patients, whose cure rate hovers around 40 percent. Patients with other forms of medulloblastoma are twice as likely to survive.
“We need new chemotherapy agents, because the current treatment often doesn’t cure,” Gajjar says. “The drugs identified in this study will hopefully close that survival gap.”
For Roussel, doing science that has the potential to help cure patients fulfills a longtime aspiration. “As a basic scientist, it is exciting to be able to translate a laboratory discovery into drugs that are now being used in a clinical trial,” Roussel says. “This is one of the most rewarding things that I’ve done.”
The St. Jude campus and culture have been deliberately designed to spark critical connections between physicians and scientists, and across scientific disciplines. “That’s what’s special about St. Jude,” Roussel says. “Everything is in one place, and people are extremely collaborative and willing to be part of big projects.”
Using new scientific findings to improve patient care sounds simple. In practice, the process, called translation, is complex. To be successful, experts across many research fields must first find each other, then work together productively for many months or years.
One key collaborator on this project was Gajjar, who helped guide the laboratory work from the perspective of a physician who sees medulloblastoma patients every day.
Shelat and others on campus also played central roles. Clinton Stewart, PharmD, and his research group in Pharmaceutical Sciences conducted laboratory experiments showing that the drug pair can pass through the blood- brain barrier to target the tumors in the right place. Scientists in Stewart’s laboratory collaborated closely with each other to collect the samples, measure the amount of drug with sophisticated instruments, and then model the drug concentrations to determine the correct doses to use in SJMB12.
Kip Guy, PhD, the chair of CBT, has been the architect of many drug discovery efforts at St. Jude. Like Gajjar, he credits the St. Jude mission with drawing people together to find cures.
“This place is an order of magnitude more mission-driven than anywhere else I’ve ever seen,” he says. “We are here because we care about the pediatric clinic. More often than not, you could ask me about a specific childhood cancer and I could list 10 people at St. Jude who could come together as a team to work on it.”
Saving children with high-risk medulloblastoma is one critical priority. There are many others. The drug discovery program at St. Jude has been built to find cures for the world’s toughest-to-treat childhood cancers by casting as wide a net as possible.
Researchers on campus have also recently teamed up against another childhood brain tumor, ependymoma, and revealed unrecognized promise in an adult cancer drug called 5-fluorouracil (5-FU).
Guy and Richard Gilbertson, MD, PhD, director of the St. Jude Comprehensive Cancer Center, spearheaded the project, which was the first large drug repurposing screen on campus. 5-FU is now being given to St. Jude patients with relapsed ependymoma in an early-stage clinical trial.
Similar projects homing in on other cancers are blossoming around campus, fueled by the early successes of these teams.
For the researchers leading these projects, repurposing known drugs is simply the first step. The screening process also provides an opportunity to assess tens of thousands of other chemicals that have never been tried in the clinic. These molecules represent uncharted territory; after careful testing and refinement, a select few may one day be shaped into completely novel therapies.
This state-of-the-art drug discovery pipeline would have sounded like science fiction when St. Jude opened in 1962. Yet, it is really just a modern embodiment of what the hospital’s founder first envisioned.
“Our academic mission is to develop new therapies,” Gajjar says. “It’s what Danny Thomas’ dream was—to build an institution where the lab and clinic were interwoven to improve cure rates for these children.”
Abridged from Promise, Summer 2014