SALT LAKE CITY— A new compound shows promise in patient leukemia samples when current treatments fail, say researchers from Huntsman Cancer Institute (HCI) at the Ï㽶ÊÓƵ of Utah (U of U). Their report appears online in Blood, the Journal of the American Society of Hematology (ASH).
"The compound we discovered, Lenaldekar, works differently than the current mainstay treatments for leukemia. It attacks two legs which many types of the disease stand on, one a biochemical pathway important for the survival of leukemia cells and the other a process that promotes cell division," says HCI investigator Nikolaus Trede, M.D., Ph.D., associate professor in the U of U's Department of Pediatrics and principal investigator of the study. "This offers hope of an alternate treatment for patients who develop resistance to standard treatment. Now intense efforts are needed to convert Lenaldekar into a drug that can be used in patients so we can conduct the clinical trials needed to obtain FDA approval."
The researchers used a novel approach that may have a broad range of potential future applications in identifying new drugs for cancer treatment. Earlier, Trede and collaborators developed a line of zebrafish in which immature T cells glow green under fluorescent light. Using this line of fish they showed that the drug dexamethasone—a mainstay of leukemia treatment in patients—eliminates immature T cells in developing zebrafish.
Based on this observation "we hypothesized that a compound that eliminated immature T cells would potentially also eliminate T cell leukemia," says Trede. "It was a risky undertaking because at the time we knew only the effect we wanted—and nothing about the mechanism the test compounds might use to eliminate immature T cells. Usually, screens for new drugs are conducted with either known targets or with drugs whose mechanism is known."
Trede explains that another advantage of using zebrafish is that the entire organism is exposed to the drug so that toxic side effects of conventional chemotherapy are easy to spot. Rather than using zebrafish as the model in which to search for active chemicals, most drug screening tests are performed on isolated targets or human cell lines.
"One problem with this method," he says, "is that these cell lines have existed for a long time, sometimes decades; they've been through many generations, and mutations have accumulated that make them very different from malignant cells in patients we treat in our practice."
The researchers only tested compounds in human cell lines once they had established in the zebrafish model that the compounds were active but also nontoxic. "The early tests with zebrafish allowed us to narrow a field of more than 26,000 compounds down to five likely candidates before we began testing in human cell lines," Trede explains. "After these tests, one compound, Lenaldekar, emerged that selectively killed leukemia cells but not other cancer cells or normal human cells."
Tests in zebrafish and mice with leukemia and in samples taken directly from patients with therapy-resistant leukemia provided confirmation that the drug is nontoxic in mammals but efficiently kills leukemia cells. "Now that we know we have an effective molecule, we're going back to identify what protein in leukemic cells Lenaldekar targets," says Trede. "And before the drug can be offered in clinical trials, further development of the proper formulations for use in humans will also be necessary."
The Blood article lists 25 co-authors from HCI, the U of U, The Ï㽶ÊÓƵ of Southern California, and the Ï㽶ÊÓƵ of Toronto. Funding from The Dana Foundation, The William-Lawrence Blanche Hughes Foundation, Marriner S. Eccles Foundation, Alex's Lemonade Stand Foundation, The James and Lynnette D. Loveland Foundation, and Huntsman Cancer Foundation via the Directors Translational Research Initiative supported the study.