Project description:Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castrate-resistant prostate cancer (CRPC), we used a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eIF4A. Zotatifin repressed tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis revealed two important translational targets: Androgen Receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solved the structure of the 5’UTRs of these oncogenic mRNAs and strikingly observed complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to radiotherapy, usually blunted by HIF1A. Therefore, ‘translatome therapy’ opens new avenues to treat the deadliest cancers.
Project description:Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castrate-resistant prostate cancer (CRPC), we used a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eIF4A. Zotatifin repressed tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis revealed two important translational targets: Androgen Receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solved the structure of the 5’UTRs of these oncogenic mRNAs and strikingly observed complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to radiotherapy, usually blunted by HIF1A. Therefore, ‘translatome therapy’ opens new avenues to treat the deadliest cancers.
Project description:Tuning protein expression by targeting RNA structure using small molecules is an unexplored avenue for cancer treatment. To understand whether this vulnerability could be therapeutically targeted in the most lethal form of prostate cancer, castrate-resistant prostate cancer (CRPC), we used a clinical small molecule, zotatifin, that targets the RNA helicase and translation factor eIF4A. Zotatifin repressed tumorigenesis in patient-derived and xenograft models and prolonged survival in vivo alongside hormone therapy. Genome-wide transcriptome, translatome, and proteomic analysis revealed two important translational targets: Androgen Receptor (AR), a key oncogene in CRPC, and hypoxia-inducible factor 1A (HIF1A), an essential cancer modulator in hypoxia. We solved the structure of the 5’UTRs of these oncogenic mRNAs and strikingly observed complex structural remodeling of these select mRNAs by this small molecule. Remarkably, tumors treated with zotatifin become more sensitive to radiotherapy, usually blunted by HIF1A. Therefore, ‘translatome therapy’ opens new avenues to treat the deadliest cancers.
Project description:Prostate cancer is the most common cancer in men and androgen receptor (AR) downstream signalings promote prostate cancer cell proliferation. PSF is a RNA binding protein which is involved in AR signaling.To investigate the effect of samll molecule, No.10-3, on the RNA binding ability of PSF, we performed RNA immunoprecipitation (RIP) sequence analysis in AR positive prostate cancer cell line long term androgen deprivation (LTAD) cells to explore the differences of PSF function to associate with RNAs in prostate cancer cells.
Project description:BAG1 is a family of polypeptides with a conserved C-terminal BAG domain that functions as a nucleotide exchange factor for the molecular chaperone HSP70. BAG1 proteins also bind to diverse cellular proteins and control several signaling processes including proteostasis, apoptosis and transcription. The largest BAG1 isoform (BAG1L) controls the activity of the androgen receptor and is upregulated in prostate cancer. Here, we show that BAG1L binds to the AR N-terminal domain (NTD) and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by targeting the BAG domain with a small molecule, 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17), downregulates AR target gene expression and blocks proliferation of AR-positive prostate cancer cells. A4B17 also inhibits tumor development in mouse xenograft models under castration conditions. A4B17 is therefore a BAG1 inhibitor with unique properties to inhibit prostate cancer growth.