Cuglievan, B. | bioRxiv Science

bioRxiv2023

BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor

BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPases of chromatin remodeling BAF (BRG1/BRM-associated factor) complexes, which enable transcription factors/co-factors to modulate gene-expressions, mediating growth, differentiation-arrest and survival of AML cells. In AML with MLL1r (MLL1 rearrangement) or mutant (mt) NPM1, although monotherapy with Menin inhibitor (MI) induces clinical remissions, most patients either fail to respond or relapse. FHD-286 is a selective BRG1/BRM inhibitor, undergoing clinical development in AML. Here, FHD-286 induced differentiation and lethality in AML cells with MLL1r or mtNPM1, reducing chromatin accessibility and repressing c-Myc, PU.1 and CDK4/6. Whereas FHD-286 monotherapy reduced AML burden, leukemia-initiating potential and improved survival, FHD-286 combinations with MI, BET inhibitor, decitabine or venetoclax was significantly more effective in reducing AML burden and improved survival, without significant toxicity, in xenograft models of AML with MLL1r or mtNPM1. These findings highlight promising FHD-286-based combinations for therapy of AML with MLL1r or mtNPM1. Statement of SignificanceInhibition of BRG1/BRM ATPases by FHD-286 reduced chromatin accessibility, repressed c-Myc, PU.1 and CDK4/6, inducing differentiation, leukemia-initiating potential and lethality in AML stem-progenitor cells. FHD-286-based combinations with Menin or BET inhibitor or decitabine reduced AML burden and improved survival in xenograft models of AML with MLL rearrangement or mutant NPM1.

cancer biology↗

bioRxiv2022

The Androgen Receptor: A Therapeutic Target in Desmoplastic Small Round Cell Sarcoma

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer. ONE SENTENCE SUMMARYWe demonstrate that DSRCT, an aggressive pediatric cancer, is an AR-driven malignancy capable of responding to androgen deprivation therapy.

cancer biology↗