US researchers have identified a new target for acute myeloid leukaemia (AML), as well as small molecules which could become the basis of a novel treatment in the future.
Various signalling pathways in the innate immune system are activated in AML, which appear to be important for the cancer’s survival. Targeting these pathways with drugs has proven challenging so far, as the various pathways provide multiple ‘escape routes’ which allow the cancer cells to resist treatment.
A study led by a team from Cincinnati Children’s Hospital has identified that many of these pathways converge on a protein called UBE2N. In their study, the team show that UBE2N is essential for the survival of a range of subtypes of AML.
As part of their research, the team identified a class of small molecules which block the function of UBE2N. This, in turn, kills AML cells in lab dishes and in mouse models, without killing healthy blood cells, the researchers say.
The study, published in Science Translational Medicine, is described as a potential breakthrough towards developing a novel therapy.
Senior author Dr Daniel Starczynowski, of the Cancer and Blood Diseases Institute at Cincinnati Children’s, said: “This is novel chemistry that has never been used in medicine for any other reason that we’re aware of.
“The team not only identified a new therapeutic target in AML and characterised its mechanism, but they also found a new small molecule that could eventually lead to a new drug.”
In this study, they found several redundant innate immune pathways that AML uses to survive all depend on the function of UBE2N. Therefore, blocking UBE2N could make it harder for the cancer cells to multiply and survive treatment.
“Not only does the new compound appear to be worth exploring to treat AML, similar dependencies on UBE2N are observed in a number of other conditions,” said Dr Starczynowski. These include solid tumour cancers such as breast, ovarian and colon cancers, as well as some chronic inflammatory disorders.
“We still have a lot more work to do,” said Dr Starczynowski. “This a compound, not a drug. It still needs to be refined and optimised before we can get it to patients.”
Source: Barreyro L, Sampson AM, Ishikawa C, Hueneman KM, Choi K, Pujato MA, Chutipongtanate S, Wyder M, Haffey WD, O'Brien E, Wunderlich M, Ramesh V, Kolb EM, Meydan C, Neelamraju Y, Bolanos LC, Christie S, Smith MA, Niederkorn M, Muto T, Kesari S, Garrett-Bakelman FE, Bartholdy B, Will B, Weirauch MT, Mulloy JC, Gul Z, Medlin S, Kovall RA, Melnick AM, Perentesis JP, Greis KD, Nurmemmedov E, Seibel WL, Starczynowski DT. (2022) “Blocking UBE2N abrogates oncogenic immune signaling in acute myeloid leukemia.” Science Translational Medicine, doi: 10.1126/scitranslmed.abb7695
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