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Researchers Develop New Drug Candidate that Shows Potential in Treating Rare Leukemia


University of Michigan Comprehensive Cancer Center researchers have developed a new potential drug candidate that shows promise against a rare type of blood cancer, as well as potential in prostate cancer.

The new drug candidate showed potential in laboratory studies against a rare type of acute leukemia. Additionally, separate studies suggest the same compound may play a role in prostate cancer treatment as well. The compound was developed in the labs of Jolanta Grembecka, PhD, and Tomasz Cierpicki, PhD, who for years have been working to identify a small-molecule inhibitor that would block the interaction between the menin protein and MLL fusion proteins that cause MLL fusion leukemia.

MLL fusion leukemia can occur in both adults and children, representing up to 10 percent of acute leukemia in adults and about 70 percent of acute leukemia in infants. Currently, treatments are not very effective, with a little over a third of patients surviving five years. According to the researchers, protein-protein interactions like the menin-MLL fusion protein interactions in leukemia are typically considered “undruggable,” meaning it can be very challenging to develop drugs that target those interactions. Grembecka said that despite the difficulty, the MLL-menin interaction remained tempting.

“In many types of cancer, you see multiple interactions and mutations that trigger the cancer. The MLL-menin interaction is a good drug target because it’s the primary driver in this type of leukemia. By blocking this interaction, it’s very likely to stop the cancer,” said Grembecka, assistant professor of pathology at the University of Michigan Medical School.

In a study, published in Cancer Cell, the researchers tested two compounds they developed in cell lines and in mice with MLL leukemia. The compounds, MI-463 and MI-503, were delivered into the blood and metabolized at a good rate, both of which are key issues in developing new drugs. An earlier of the compound was previously tested by the researchers. The earlier version did show promise, however to make the drug more attractive for use in humans, the researchers substantially improved its potency and many of its pharmacologic properties.

“Against all odds, we decided to explore finding a way to block the MLL-menin interaction with small molecules. From nothing, we have been able to identify and greatly improve a compound and show that it’s got valuable potential in blocking MLL fusion leukemia in animal models,” said Cierpicki, assistant professor of pathology at the U-M Medical School.

Additionally, U-M prostate cancer researchers discovered that menin and MLL play a role in androgen receptor signaling, a key driver of prostate cancer. In a study, published in Nature Medicine, the researchers studied the same MLL-menin inhibitors against castration resistant prostate cancer cells and mice models.

“Our study suggests that this MLL-menin inhibitor might also have a potential role in a more common solid tumor, in this case prostate cancer,” said Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and the senior author on the Nature Medicine paper.

The researchers noted that the compounds must be tested further in the laboratory before any clinical trials could be considered. Grembecka and Cierpicki’s labs are looking at further refinements and more advanced testing of their inhibitors. Additionally, Chinnaiyan’s team will continue to study the role of MLL in castration resistant prostate cancer.

Sources:

Cancer Cell“Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo,” published March 26, 2015

Nature Medicine, “Targeting the MLL complex in castration resistant prostate cancer,” published March 30, 2015

Last updated: 4/1/15; 1:30pm EST

 

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