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WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

ABSTRACT: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche and identified WDR5 as indispensable for this population. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. Genetic and pharmacologic inhibition of WDR5 reduced growth and self-renewal of CSCs as well as CSC-mediated tumor growth. Further, WDR5 inhibitors blocked WRAD complex assembly, reduced H3K4 trimethylation, and inhibited tumor growth. These findings highlight the role of WDR5 and the WRAD complex for maintaining the CSC state and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199110 | GEO | 2023/01/26

REPOSITORIES: GEO

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A Phase I/II Study of Active Immunotherapy With Cancer Stem Cells Vaccine for Colorectal Cancer

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Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and well-established imide:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling also revealed targets of both WDR5 and imide:CRBN to be repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.

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Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics [ChIP-Seq]

2022-05-15 | GSE175544 | GEO

Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics [GRO-Seq]

Project description:WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and the well-established IMiDs:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling revealed that gene targets of WDR5 and IMiDs:CRBN were both repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a matched VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.

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Expression profiles of CD24-/CD44+/ESA+ population in MDA-MB-231 and its highly metastatic variants.

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2011-11-30 | E-GEOD-25976 | biostudies-arrayexpress

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