New Study Identifies Promising Inhibitor Combination for Hard-to-Treat Leukemia Subtypes

Assistant Professor of Biomedical Sciences M. Andrés Blanco, PhD, from the University of Pennsylvania’s School of Veterinary Medicine (Penn Vet) and investigators from the Universities of Oxford, Helsinki, and California at San Diego identified a promising strategy to overcome treatment resistance in acute myeloid luekemia (AML), one of the most aggressive forms of blood cancer.

AML occurs when bone marrow produces substantial amounts of abnormal white blood cells. According to the American Cancer Society, AML accounts for one-third of leukemias in adults, and it can spread rapidly through the body. Differentiation therapy, a cancer treatment that prompts cancer cells to become less aggressive thereby reducing or stopping their proliferation, is curative for the acute promyelocytic leukemia (APL) subtype of AML, but not for the other eight non-APL subtypes (FAB classification).

According to the study published in Nature, Oxford University’s Amir Hosseini, PhD, et al., utilized a high-throughput screening strategy to identify small molecule inhibitors that synergize with inhibitors of the histone demethylase LSD1 to induce terminal differentiation of acute myeloid leukemia cells. The authors found that combinatorial inhibition glycogen synthase kinase 3 (GSK-3) and LSD1 synergistically induces terminal differentiation in non-APL AML cell lines and patient samples.

Mechanistically, it was found that, B-catenin – which is stabilized by GSK-3 inhibition – surprisingly does not activate the WNT pathway but instead complexes with alternative transcription factors to conduct a pro-differentiation interferon response that is initiated by LSD1 inhibition. In pre-clinical models, combinatorial treatment with LSD1 and GSK-3 inhibitors dramatically extended lifespan of AMLs with DNMT3A mutations. As a result of these findings, the researchers nominated this novel inhibitor combination for the treatment of human non-APL subtypes of AML.

“These findings present a potential new avenue for differentiation therapy in AML subtypes that have resisted such approaches,” said Blanco, corresponding author of the study. “This study provides a compelling rationale for testing dual LSD1 and GSK-3 inhibition as a therapeutic technique for humans with non-APL AML subtypes, offering hope for better outcomes with this disease.”