St. Baldrick’s Researcher Uses Novel Drug Screening Method for Potential New ALL Treatments

by Rebecca Bernot, St. Baldrick's Foundation
December 13, 2013

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Historically, scientists have largely relied on nature as a source for treatments for various ailments. The modern-day antibiotic penicillin, for example, is derived from mold. Opium made from poppy seeds was cultivated and used for its pain relieving properties by ancient civilizations, and it is still used today to make morphine, codeine, and other painkillers in the opioid class.

Now, thanks to advances in modern chemistry, scientists are able to synthesize hundreds of thousands of known drug compounds and store them in vast chemical libraries. With the aid of highly technical robots and computers, researchers can test the entire library for effectiveness in treating a certain disease in a process known as high-throughput screening.

The problem that arises with these types of chemical screens is that we don’t always know how the compounds work. There may be thousands of drugs that are effective in killing cancer cells, but if we don’t know how or why they work, then we don’t know how to effectively use them, and we can’t predict what kind of damage they could cause to the healthy parts of the body.

Michael Wei, M.D., Ph.D., instructor in pediatric hematology – oncology at Stanford University and a St. Baldrick’s Scholar, found a way to get around that problem.

In his research focused on improving survival for pediatric high-risk B cell acute lymphoblastic leukemia (ALL), he and his colleagues at Stanford, including Christina Matheny, Ph.D., and Michael Cleary, M.D., used a combination high-throughput screening method to identify a novel class of drugs that could improve patient outcomes for this aggressive subtype of leukemia.

Their discoveries were published in the November 21 issue of Chemistry & Biology, and Dr. Wei presented the research at the annual meeting of the American Society of Hematology last week.

Double high-throughput screening

In simple terms, Dr. Wei says, “We test drugs for their ability to kill cancer cells and then determine how they kill cancer cells.”

The first phase of the screening was a type of chemical screen. Over 100,000 compounds were tested for their effectiveness in killing leukemia cells, and the results yielded multiple lead compounds. The most promising lead compound was then subjected to a second screen — a genetic screen — to identify the gene the drug interferes with.


A screening robot at the Conrad Prebys Center for Chemical Genomics. Photo by Josh Baxt.

Imagine you had access to a library that coded the entire human genome — all the DNA in the human body. And imagine that you had a tool that could block — or “knock down,” as scientists say — one gene at a time. Then imagine you had an experimental drug that you know will kill cancer cells, but before you can give it to children with cancer, you need to find out how it works. So you take a bunch of cancer cells, you use your tool to knock down one gene, and you treat the cancer cells with your experimental drug. The cancer cells die, as expected. So you use your tool to knock down a different gene and you do it again. And again. And again.

Finally, in one of these rounds, the cancer cells die even faster. You stop and you look to see which gene was knocked down. Since the drug was more effective in killing the cells when that gene was knocked down, it likely means that your drug is targeting that gene.

“Less expression of the gene requires less drug to effectively kill cells,” Dr. Wei explains. “We found that knockdown of our gene sensitized cells to our drug. Because it’s a knockdown, there is less of the gene product around, requiring less of the drug to inhibit it.”


Dr. Wei in the lab.

Dr. Wei and his team had large libraries of tools that enabled them to do the testing simultaneously. Their “tools” were short hairpin RNAs, strings of RNA engineered to block the function of a specific gene.

The genetic screen showed them that the drug was working on NAMPT, a key enzyme in cancer cell metabolism. Further testing confirmed that NAMPT was, indeed, the drug’s target in the cell.

“This mechanism of action is distinct from other current chemotherapy agents and represents a potential new way to treat ALL,” according to Dr. Wei.

Their tests also showed that the drug could kill other cancer cells. “We found that it has broader activity, not just in leukemia,” Dr. Wei indicates, explaining that they have reason to believe the drug could also be used to treat other forms of adult and pediatric cancers.

A new class of drugs

Dr. Wei and his team’s discovery wasn’t just a one-and-done deal. “We found a new class of these inhibitors,” he says. So while their focus is on one drug in this class, there are multiple compounds and derivatives that can also be tested to see if some work better in certain cancers than others.

“We believe this drug is very promising and are optimistic about eventually bringing it to clinical use,” Dr. Wei says.

Their plan is to test their drug for use with other existing therapies. “Typically, single-agent therapies lead to resistance, so we’d ideally want to use this in combination with other drugs,” Dr. Wei explains.

“We believe this drug is very promising and are optimistic about eventually bringing it to clinical use,” he adds. The drug development process is lengthy, and a new drug requires thorough testing before it can enter clinical trials, so it could be years before kids with leukemia can benefit from this new therapy. But pharmaceutical companies have shown interest in NAMPT inhibitors in recent years, so Dr. Wei is talking to some companies to accelerate development of his drug.

A message to supporters

Dr. Wei’s project is in the early stages of research, an area where financial support is particularly hard to come by in the already-underfunded arena of childhood cancer research. But the advancement of these ideas is absolutely critical to the development of new and better treatments for kids with cancer.

“I would like to sincerely thank all of the donors and volunteers who contributed so much time and effort to make St. Baldrick’s funding for children’s cancer research possible,” Dr. Wei says. “Without the Foundation’s support, this project would not have been possible.”

Your support makes pediatric oncology research happen. Make a donation today.