UF Health Cancer Institute researchers have created a drug that effectively kills aggressive leukemia cells by targeting two proteins that promote the cancer’s growth.
“We discovered a new function of one protein in promoting the growth of acute myeloid leukemia cells,” said Chandra Maharjan, Ph.D., a research assistant scientist in the lab of Weizhou Zhang, Ph.D., and lead author of the study, published July 30 in Oncogene. “That allowed us to develop a novel drug that binds and degrades two proteins at the same time. It killed leukemia cells efficiently both in mouse models and human samples.”
Acute myeloid leukemia, or AML, is an aggressive blood cancer with among the worst survival rates of all leukemias. It is one of the leading causes of cancer-related deaths in children. Despite advances in treatments, many patients still relapse or do not respond to standard chemotherapy treatment, particularly older adults.
The researchers found that in patients with poor outcomes, two proteins — IKKβ and NR4A1 — work together to sustain cancerous cells. But drugs that inhibit IKKβ have been shown to cause serious side effects, limiting their development as potential therapies. And researchers previously thought degrading NR4A1 was not a viable option.
“There was an idea in the field that NR4A1 suppresses acute myeloid leukemia, but we provide novel evidence that it can also promote certain subtypes to grow and survive,” Maharjan said. “People thought it was generally a good guy for this cancer type, but we found it’s actually a bad guy for certain subtypes of AML. This discovery gave us the opportunity to develop a single agent that can degrade both NR4A1 and IKKβ, leading to more pronounced anti-cancer effects.”
Working closely with UF medicinal chemists in the lab of Guangrong Zheng, Ph.D., the researchers developed and patented the drug, called a proteolysis-targeting chimera, or PROTAC.
PROTACs are an emerging type of small-molecule drug that have shown promise in cancer and other diseases. They work by delivering a target protein to the cell’s own disposal machinery where it is then destroyed. Zhang and Zheng have been working on developing novel therapeutics in the PROTAC field, primarily for breast, melanoma and other cancers. The two were part of a UF team that developed the BCL-XL-targeting PROTAC, the first of its kind to receive FDA clearance for testing in an early clinical trial that paved the way for further larger ongoing trials.
They collaborated on the new study for the first time with Jatinder Lamba, Ph.D., a professor and associate dean in the UF College of Pharmacy who is an expert on multi-omics approaches to improve the safety and effectiveness of clinical drugs in blood cancers.
“It’s a perfect situation with complementary expertise because my work focuses on the patient side in AML and Dr. Zhang’s lab has extensive expertise in animal models,” said Lamba, co-leader of the Cancer Institute’s Cancer Targeting and Therapeutics research program.
Zhang said the new drug killed leukemia cells more efficiently than other drugs his team has tested. More testing will be needed to move it to clinical trials in humans.
“We’re planning to test the combination of this compound with other therapeutics in AML, as well as characterize which patients benefit from this treatment,” said Zhang, co-leader of the Cancer Institute’s Mechanisms of Oncogenesis research program and a professor and vice chair of research in the Department of Pathology, Immunology & Laboratory Medicine. “We predict it could be combined with current therapies to more effectively kill AML cells.”
The study received funding from the Department of Defense, National Institutes of Health, UF Health Cancer Institute and an endowment fund from the Dr. and Mrs. James Robert Spenser Family.
