Study Reveals Target of Leukemia Drug

A new study reveals that all-trans retinoic acid (ATRA), currently used to treat acute promyelocytic leukemia (APL), may be effective in treating particularly aggressive or drug-resistant cancers by degrading the Pin1 enzyme, a key regulator of many oncogenic pathways and cancer stem cells.

Unlike other Pin1 inhibitors tested in cell models and animals, ATRA infiltrates cells and blocks multiple oncogenic pathways amplified by Pin1, according to findings published in Nature Medicine. At the same time, it inhibits the expansion and tumorigenesis of leukemia stem cells, which drive APL.

“Our paper offers a promising new approach for targeting a Pin1-dependent common oncogenic mechanism to block multiple cancer-driving pathways and to eliminate cancer stem cells,” says the study's co–senior author Kun Ping Lu, MD, PhD, director of translational therapeutics in the Cancer Research Institute at Beth Israel Deaconess Medical Center and a professor of medicine at Harvard Medical School, both in Boston, MA. “It also provides a rationale for developing more potent and specific Pin1-targeted ATRA variants for cancer treatment,” says Lu, who codiscovered Pin1 in 1996.

It had been thought that ATRA successfully treated APL by inducing APL stem cells to differentiate and degrading the disease-causing fusion oncogene PML–RARα. However, they did not know that Pin1 is a critical target for inducing that process.

Lu and his team made the discovery by screening more than 8,000 chemical compounds, including approved drugs and bioactive compounds, in a competition binding assay, using a previously identified Pin1 substrate-mimicking peptide inhibitor as a probe. They identified the compound cis-retinoic acid, which has the same chemical formula as ATRA but a different chemical structure. They then compared the two compounds for binding to Pin1.

“We found that Pin1 prefers binding to ATRA and that cis-retinoic acid needs to convert to ATRA in order to bind to Pin1,” says Lu. “That told us that a very specific 3- dimensional structure is required for an inhibitor to go into the active Pin1 site.”

After demonstrating that ATRA targets Pin1 to degrade PML–RARα and treat APL in cell and animal models as well as in patients, the researchers tested ATRA in 48 human samples of triple-negative breast cancer, one of many cancers in which Pin1 is overexpressed, and found that the drug successfully inhibited cancer cell growth. However, results from an earlier, unrelated phase II human trial suggest that ATRA has detectable efficacy but is less effective for advanced breast cancer than APL.

“The current formulation of ATRA has a very short half-life of 45 minutes in humans,” says Lu. “That may be one major reason why it can effectively treat APL but may not be as effective against solid tumors, because it takes longer for the drug to get into the tumor cells.”

Lu is now working on increasing the effectiveness of Pin1 inhibitors, including developing a more potent formulation of ATRA with a longer half-life.

“We are also screening for other new Pin1 inhibitors using our high-throughput screening,” he says. “These more potent Pin1 inhibitors may be able to target many ‘dream targets’ that are not currently druggable.”