Pediatric Oncology Director and leukemia expert Donald Small understands the importance of bridging the laboratory and clinic to bring new drugs to patients. Working with Mark Levis in the laboratory and Doug Smith and Patrick Brown in the clinic, his FLT3 (pronounced flit three) discovery brought a new leukemia drug to adult and pediatric patients. Small’s research of hematopoiesis— how blood cells grow and expand—led him to clone the first human FLT3 gene. Next, he proved that it was very active in acute myeloid leukemia and some cases of acute lymphoid leukemia. In fact, FLT3 turned out to be the most frequently mutated gene in acute myeloid leukemia. About one-third of patients diagnosed had the mutation— an alteration that made it almost impossible to cure them.

“Having a FLT3 mutation reduces the chances of curing an AML patient from about 50 percent to less than 20 percent,” says Small. He had a target in FLT3, and if he could find a drug to neutralize it, Small believed combining such a drug with chemotherapy would improve cure rates for these patients, at least to rates of nonFLT3 AML and potentially even better. Searching for such a drug proved to be a laborious, time-consuming process. He began by screening a library of more than 4,000 drugs known to target the family of proteins to which FLT3 belonged. He set up 96 wells, filled each one with FLT3-positive leukemia cells and tested each one of the 4,000 drugs to see if any of them killed the cancer cells.

One by one, a specific amount of each drug was placed in the wells. “If the color changed, it meant the drug didn’t work. If there was no color change, we knew we had an active drug,” says Small. When he found a drug that worked, he systematically decreased the amount put in the wells to see how low he could take the drug and still get an anticancer response. It wasn’t high-tech, but at the time, it was the only way to get the job done, Small says. Now, there is an automated drug discovery tool called high through put screening that allows researchers to quickly perform millions of chemical, genetic or pharmacological tests, but in the late 1990s when Small began his research, low-tech was the only option for most university-based researchers. When all of his tests were completed, CEP-701 stood out as the best drug. With a FLT3 inhibitor identified, Levis joined Small and began testing the drug in his laboratory and animal models to help figure out how to best use the drug in patients.

Since the drug had already been tested in clinical trials, this eliminated many of the FDA hurdles needed to move a drug into clinical trials, and Small and Levis partnered with Smith to take it to patients. As Berger points out, drug discovery is not a single path. There is much back and forth between the laboratory and the clinic, following the science and the clinical data rather than a predetermined and straightforward path to get to the right drug. The essential ingredient of scientist/clinician collaboration is the reason the Kimmel Cancer Center is the perfect environment for drug discovery.

“We’re not as big as other places, but we’re really, really good at working together,” says Smith. “We’re also outstanding at basic science, clinical research and clinical practice, and that’s the translational machinery that makes drug discovery and development possible.” When Smith took CEP-701to patients, it was a mixed bag of results. The drug cleared leukemia cells out of the bloodstream and, in some patients, out of the bone marrow where new blood cells are made and leukemia originates. But, the responses were temporary, a result not completely unexpected in phase I trials where the sickest of the sick are typically treated. Levis developed an assay for FLT3, a test that tells if the drug is actually hitting its intended target. “We were excited to see it was killing leukemia cells, and we had an assay to measure it, but we still needed to dig deeper,” says Levis.

The group’s goal was to get patients into remission using a combination of a FLT3 inhibitor and chemotherapy so they could receive a bone marrow transplant, a potentially curative therapy that replaces the patient’s diseased bone marrow with healthy marrow from a donor. Levis’ assay proved the drug was hitting its target, but in larger studies, it also showed it had a serious flaw. The target was a good one, but in many patients, the drug’s chemistry allowed the proteins in their bodies to suck up too much of the drug before it hit its target. Levis went to the inpatient unit, watched patients take CEP-701, got blood samples from patients, carried the blood back to his laboratory himself and then used his assay to test the samples to see if the drug was hitting the FLT3 target. If his assay showed the drug was hitting FLT3, Levis knew that patient would respond to treatment.

“The correlation between the drug hitting the target and clinical response was key,” says Smith. “You can’t get anymore bench to bedside than that.” In that not-so-straight path to a drug, it often takes many chemical modifications to get it right. Newer formulations of FLT3 inhibitors, built upon Small and Levis’ science and other clinical studies, have overcome the limitations of the original drug. Levis is considered the worldwide expert on FLT3 activity. He, and others around the world, continue to work on these better versions of FLT3 inhibitors, and there are several better drugs now being studied in patients. Brown would like to study the newer, more potent versions of FLT3 inhibitors in pediatric leukemia patients, particularly in a subset of leukemia patients he believes would respond well, but currently, studies are limited mostly to adults.

Levis’ assay is considered the gold standard, and every major FLT3 drug is sent to him to see if it works. “We’ve now demonstrated in patients, through studies here and at other centers, that people who got FLT3 inhibitors— with or without bone marrow transplant— did better,” says Smith. “Now we have to continue our clinical trials with the newer versions of the drugs.” Smith says FLT3 inhibitors are being studied in combination with other targeted therapies to see if they have broader uses. “Ultimately, a good FLT3 inhibitor in the right combination therapy could replace bone marrow transplant in certain patients,” says Smith. “We would love to give patients a cocktail of a few targeted therapies and no toxic chemotherapy, and eliminate the need for other treatments. That’s the goal, but we’re not quite there yet.” As a cancer clinician who connects the laboratory to the clinic, Smith finds the drug discovery process one of the most rewarding. “I love having something new to offer my patients,” he says. “It’s exciting to see a discovery in the laboratory move ahead and become a new drug I can offer to patients.”