A novel treatment strategy
Transcription factors are historically difficult to develop treatments against. However, their interaction with other proteins provides an opportunity to target their protein partners to disrupt their activity.
Using genetic methods and a compound that inhibits KDM4B in the lab, the researchers were able to substantially delay tumor growth. Combining KDM4B inhibition with currently used chemotherapy regimens caused tumors to shrink in preclinical xenograft models of the disease.
"We looked for epigenetic upstream regulators that can regulate these transcription factors and identified KDM4 specifically as one of these regulators, which is in itself novel," said co-first author Ahmed Abu-Zaid, St. Jude Department of Surgery. "We also tested a targeted therapy in this cancer model, in combination with chemotherapy, which demonstrated a very effective anti-cancer effect. KDM4 inhibition has not been tried in this disease, so that is also exciting."
There is a targeted inhibitor of KDM4B that is currently being clinically tested for adult colon cancer. Additional research is needed before the approach can be translated into a clinical trial for children with rhabdomyosarcoma.
Authors and funding
Additional authors are Tingting Wang and Ruoning Wang, Nationwide Children's Hospital; Helin Feng, the Fourth Hospital of Hebei Medical University, Shijiazhuang China; Eleanor Chen, University of Washington; Peter Lewis, University of Wisconsin-Madison; and Jie Fang, Qiong Wu, Waise Quarni, Ying Shao, Lily Maxham, Alireza Abdolvahabi, Mi-Kyung Yun, Sivaraja Vaithiyalingam, Haiyan Tan, John Bowling, Victoria Honnell, Brandon Young, Yian Guo, Richa Bajpai, Shondra Pruett-Miller, Gerard Grosveld, Mark Hatley, Beisi Xu, Yiping Fan, Gang Wu, Taosheng Chen, Zoran Rankovic, Yimi Li, Andrew Murphy, John Easton, Junmin Peng, Xiang Chen, Stephen White and Andrew Davidoff of St. Jude.
The study was supported by an American Cancer Society Research Scholar award (130421-RSG-17-071-01-TGB), grants from the National Cancer Institute (R03CA212802-01A1 and 1R01CA229739-01), the National Institutes of Health (CA021765) and ALSAC, the fundraising and awareness organization of St. Jude.
Read the full text of the Science Translational Medicine article:
Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma
Science Translational Medicine, published July 13, 2022
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