KDM3B inhibitors disrupt PAX3-FOXO1 oncogenic activity in fusion positive rhabdomyosarcoma.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA907384 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. We screened 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, PFI-63. RNA-seq, ATAC-seq, and docking analyses implicated histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirmed the inhibition of multiple KDMs with highest selectivity for KDM3B. Structural similarity search of PFI-63 identified PFI-90 with improved solubility and potency. Biophysical binding of PFI-90 to KDM3B was demonstrated using NMR and SPR. PFI-90 suppressed the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopied PFI-90 effects. Thus, we report novel KDM inhibitors with highest specificity for KDM3B. Its potent suppression of PAX3-FOXO1 activity can be exploited as a new therapeutic approach for FP-RMS and other transcriptionally driven cancers.
2023-12-31 | GSE219199 | GEO
Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.
2021-09-16 | PXD022187 | Pride
Project description:Interrogation of microRNA expression and regulation by PAX3-FOXO1 in Fusion-Positive Rhabdomyosarcoma.
2018-01-26 | GSE97553 | GEO
Project description:PAX3-FOXO1 is a fusion transcription factor characteristic for the majority of alveolar rhabdomyosarcoma tumors. It is the main oncogenic driver and deregulates expression of PAX3 target genes. The PAX3-FOXO1 target gene signature was determined in the Rh4 alveolar rhabdomyosarcoma cell line.
2015-09-29 | GSE73483 | GEO
Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.
2022-09-06 | GSE157093 | GEO
Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.
2022-09-06 | GSE157092 | GEO
Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.
2022-09-06 | GSE157094 | GEO
Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
2022-09-06 | GSE201224 | GEO
Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
2022-09-06 | GSE198754 | GEO
Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
2022-09-06 | GSE198755 | GEO