Abstract
Abstract
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target for cancer therapy as they usually do not bear druggable pockets. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3-FOXO1 or its variant PAX7-FOXO1 fusion oncoprotein. Even with intensive chemotherapy and radiotherapy, the 5-year survival for fusion positive aRMS is poor with no significant improvement in over recent decades. Here we show that PAX3-FOXO1 function is dependent on histone demethylase KDM4B, a potential therapeutic vulnerability for aRMS. KDM4B is highly expressed in PAX3-FOXO1-positive aRMS and is associated with late stage disease. KDM4B physically interacts with PAX3-FOXO1 via its JmjN and TUDOR domains. Genetic depletion and pharmacologic inhibition of KDM4B with a novel inhibitor QC6352 significantly delay tumor growth, impact the expression of FAX3-FOXO1 targets such as MYOD1 and FGFR4, and reduce chromatin accessibility of PAX3-FOXO1 target genes in accordance with the changes of KDM4B substrates such as H3K9me3. Combination of QC6352 with chemotherapy lead to significant xenograft regression and extended mouse survival in cell line- and PDX- based preclinical aRMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3-FOXO-driven aRMS, providing pre-clinical data for a clinal trial combining the KDM4 inhibitor with standard chemotherapy for high-risk aRMS.
Citation Format: Jun Yang, Shivendra Singh, Ahmed Abu-Zaid, Jie Fang, Andrew Davidoff. Targeting histone demethylase KDM4 for cancers driven by chimeric transcription factors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B015. doi:10.1158/1535-7163.TARG-19-B015