Scientists identify novel combination therapy approach to treat pediatric acute myeloid leukemia

Scientists at St. Jude Children’s Research Hospital and Dana-Farber Cancer Institute today report the identification of a novel combination therapy approach to treat pediatric acute myeloid leukemia (AML). Standard treatment is often ineffective against AML, a cancer that commonly relapses with poor prognosis, particularly when the disease is fueled by fusion proteins involving NUP98. The researchers documented how these fusions drive disease, discovering a protein complex required to express cancer-promoting genes. When they targeted the complex alone or in combination with another anticancer drug, survival significantly increased in AML model systems. The findings were published yesterday in Cancer Discovery, a journal of the American Association for Cancer Research.

We have made a major advance in our understanding of these difficult-to-treat leukemias. We used that knowledge to provide a strong clinical rationale to try this combined approach that had striking results.”

Charles Mullighan, MBBS, MD, senior co-corresponding author, St. Jude Department of Pathology

The scientists combined a drug that stops menin, a protein involved in controlling leukemic gene expression, with one that targets the acetyltransferases MOZ/KAT6A and HBO1/KAT7, the complex they found interacts with NUP98 fusions. The drug targeting the complex alone greatly increased survival in patient-derived mouse models, but the combination therapy had an even larger effect.

“We found this complex is targetable with an inhibitor that interacts synergistically with menin inhibition, even in relapsed disease,” Mullighan said. “With such encouraging results, this combination should be evaluated clinically, especially in patients whose cancer is resistant to menin inhibition.”

Identifying a complex vulnerability in childhood AML

Finding vulnerabilities in pediatric AML driven by NUP98 fusions has been challenging. A fusion oncoprotein comprises a pair of fused proteins, usually due to chromosomal rearrangements, often giving the hybrid new functions that can promote cancer-driving genes. Because the two original proteins still exist in the body and may have essential functions, targeting them directly can cause adverse side effects. Scientists have looked for a workaround, targeting the proteins that fusions interact with instead.

Previous research found that targeting menin, a molecule that NUP98 fusions use to promote oncogenes, is helpful – but not curative – in NUP98-rearranged leukemia. Therefore, the researchers systematically looked at proteins interacting with NUP98 fusions and DNA in AML models to find another vulnerability. After identifying the proteins interacting with NUP98 fusion proteins, they used genome editing to inactivate each gene and determine which ones the cancer depends on. In this case, they identified MOZ/KAT6A and HBO1/KAT7, which help form a complex that activates pro-cancer gene expression.

“We found NUP98 fusions drive leukemia by assembling these proteins in a complex to switch on the expression of genes that turn normal cells into leukemia cells,” Mullighan said. “We showed these inhibitors can stop the assembly of the switch, preventing activation of these cancer-driving genes, which may be a novel therapeutic vulnerability in AML.”

Authors and funding

The study’s first authors are Nicole Michmerhuizen, St. Jude, and Emily Heikamp, Dana-Farber Cancer Institute. The study’s other co-corresponding author is Scott Armstrong, Dana-Farber Cancer Institute. The study’s other authors are Ilaria Iacobucci, Masayuki Umeda, Bright Arthur, Vibhor Mishra, Chun Shik Park, Danika Di Giacomo, Ryan Hiltenbrand, Qingsong Gao, Sandi Radko-Juettner, Josi Lott, Pradyuamna Baviskar, Pablo Portola, Aurelie Claquin, David Baggett, Bappaditya Chandra, Ali Khalighifar, Hongling Huang, Peipei Zhou, Lingyun Long, Hao Shi, Yu Sun, Huiyun Wu, Stanley Pounds, Laura Janke, Richard Kriwacki, Hongbo Chi and Jeffery Klco, St. Jude; Cynthia Martucci, Varsha Subramanyam, Charlie Hatton and Daniela Wenge, Dana-Farber Cancer Institute; Evangelia Papachristou, Chandra Chilamakuri and Clive D’Santos, University of Cambridge; Francisca Vitorino, Joanna Gongora and Benjamin Garcia, Washington University in St. Louis; and Alex Kentsis, Memorial Sloan Kettering Cancer Center.

The study was supported by grants from the National Cancer Institute (P30CA021765, P30CA06516, P30CA008748, U54CA243124, R01CA259273, P01CA066996, R01CA246125, R01CA204396, F32CA261011, K99CA283256, K08CA279891, T32CA236748, R35CA197695 and R35CA253188), the Burroughs Wellcome Fund (Career Award for Medical Scientists), the St. Jude Chromatin Collaborative, the Neoma Boadway Fellowship from St. Jude, Cookies for Kids’ Cancer, the Rose Family Fellowship, Hyundai Hope on Wheels, the Children’s Cancer Research Fund, the Charles H. Hood Foundation, the American Society of Hematology, the National Recovery and Resilience Plan of the Italian Ministry of University and Research funded by the European Union, the Leukemia & Lymphoma Society, Break Through Cancer and ALSAC, the fundraising and awareness organization of St. Jude.