2 new molecules help destroy leukemia cells by targeting protein key to tumor 'seeds'

Relapses in acute myeloid leukemia (AML), the white blood cell cancer that affects blood and bone marrow, remain an obstacle despite new treatments, as the average five-year survival rate sits at 25%. Now, researchers say they’ve found two small molecules that could inhibit a key protein.

Researchers found the enzyme UBE2N aided in keeping the “seeds” for leukemia tumors alive, specifically helping leukemic hematopoietic stem and progenitor cells, or HSPCs. Those cells are core reasons for why some current treatments fail and, in turn, lead AML to recur in patients.

A team at Cincinnati Children’s Hospital Medical Center found two small-molecule inhibitors that go after UBE2N. They interfere with the protein’s enzymatic activity and could pave the way for new treatment options across AML and various other uses.

“We anticipate that the utility of UBE2N inhibitors can be extended beyond AML and used as anti-inflammatory agents, direct anticancer therapy and enhancers of antitumor immune responses,” the researchers published this month in the journal Science Translational Medicine.

One inhibitor, dubbed UC-764864, squashed AML cells in culture and did not wreak havoc on healthy HSPCs that showed no leukemic properties. A second inhibitor, aptly named in successive number order, UC-764865, tamped down the leukemic burden in mice by as much as 70% in bone marrow, which helped extend the survival of the mice with “aggressive patient-derived leukemia.” The molecule was well tolerated, the team reported.

Meanwhile, scientists at Beckman Research Institute of City of Hope found an “attractive target” for new treatments for patients with AML. The researchers found that METTL16—part of the N6-methyladenosine (m6A) family, characterized as “the most prevalent internal decorations in mammalian mRNA"—plays a central role in the development and proliferation of AML.

The researchers deemed METTL16 “one of the most essential genes for the survival of AMLs,” according to their abstract for an April presentation at the American Association for Cancer Research Annual Meeting. A driver of leukemia production, METTL16 was found to be more necessary to AML cells than other members of the m6A complex, namely METTL3/14, the team wrote in the abstract, along with collaborators at The First Affiliated Hospital of Sun Yat-sen University in Guangzhou, China, and Tongji University in Monrovia, China.

Using the famed CRISPR/Cas9 as a screening tool, the researchers found METTL16 is more prevalent in patients with AML than in those without. In bone marrow transplantation, xenograft and patient-derived xenograft models, the researchers showed depletion of METTL16 “dramatically inhibited AML progression” and led to longer survival in mice.

Recent research around AML might also lead to new treatment options. A specific portion of the protein WT1, the region 37-45, could serve as a site for engineered T-cell therapies to target, researchers at the Fred Hutchinson Cancer Research Center published last month in Science Translational Medicine.

The broader WT1 region is being targeted by Intellia Therapeutics’ CRISPR-based TCR T-cell therapy, named NTLA-5001. The treatment snagged orphan-drug designation earlier this month after entering a phase 1/2a clinical trial in patients with AML March 1.