Therapeutic targeting of splicing in aggressive prostate cancer
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ABSTRACT:
PROVIDER: PRJNA527978 | ENA |
REPOSITORIES: ENA
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Project description:Androgen deprivation therapy (ADT) is the main therapeutic regimen for patients with advanced prostate cancer (PCa). However, most treated patients invariably develop the castration-resistant disease (i.e., CRPC). Mechanisms underlying CRPC development and maintenance remain poorly understood. Recent studies have established splicing dysregulation as a new molecular hallmark of cancer. However, the functional and clinical relevance of such misregulation have not been systematically explored in PCa. Experimentally, we show that splicing modulator, E7107, can significantly inhibits CRPC cell growth both in vitro and in vivo. To determine the mechanistic origins of therapeutic effect of E7107 in vitro, we treated AR+ LNCaP and AR- PC3 cells with DMSO or E7107 at 10nM for 6 h, followed by deep RNA-seq analysis of rRNA-depleted total RNAs isolated from biological triplicates. Furthermore, to evaluate the activity of E7107 against CRPC in vivo, we utilized Enzalutamide-resistant LAPC9-AI (androgen-independent) and PC3 models. RNA-seq experiments we performed on tumors exactly 4 h after the fifth injection of E7107 (5mg/kg/day, 5-days injection considered as 1-dose treatment). Five tumors were included for each group (vehicle or E7107) for deep RNA-seq.
2020-03-04 | GSE128515 | GEO
Project description:The landscape of alternative splicing in aggressive prostate cancers
| PRJNA594270 | ENA
Project description:We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known genetic driver alterations. To do so, we compiled a meta-dataset comprised of RNA-Seq samples from publicly available sources representing a range of phenotypes from normal tissue to drug resistant metastases. We subjected these samples to exon-level analysis with purpose-built software. We then correlated transcriptional signatures of cancer driver pathways with these alternative splicing events and discovered that Myc signaling was correlated with incorporation of a set of cassette exons found in RNA binding proteins. We experimentally verified this finding in a human prostate cell transformation assay. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA processing by controlling the incorporation of nonsense mediated decay-determinant exons in RNA binding proteins.
2019-12-10 | GSE141633 | GEO
Project description:Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation
| PRJNA509783 | ENA
Project description:Clinical management of prostate cancer remains a significant challenge due to the lack of available tests for guiding treatment decisions. The blood Prostate-Specific Antigen (PSA) test has facilitated early detection and intervention of prostate cancer. However, blood PSA levels are less effective in distinguishing aggressive from indolent prostate cancers and other benign prostatic diseases. Thus, the development of novel approaches specific for prostate cancer that can differentiate aggressive from indolent disease remains an urgent medical need. In the current study, we evaluated urine specimens from prostate cancer patients instead of serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the aim of identifying effective prostate cancer biomarkers. Glycoproteins from urine samples of prostate cancer patients with different Gleason scores were characterized via solid phase extraction of N-linked glycosite-containing peptides and LC-MS/MS. In total, 2923 unique glycosite-containing peptides were identified. Comparison of urine-based glycoproteins with those identified from aggressive and non-aggressive prostate cancer tissues as well as sera from prostate cancer patients revealed that the majority of aggressive prostate cancer-associated glycoproteins were more readily detected in patient urine than serum samples. Our data collectively indicate that urine provides a highly reliable source for biomarker testing in patients with aggressive prostate cancer.
2022-02-28 | PXD004495 | Pride
Project description:Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. We performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy. We found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness. We further generated a 91-gene basal signature and applied it to gene expression datasets from patients with organ-confined or castration-resistant, metastatic prostate cancer. Metastatic prostate cancer was more enriched for the basal stem cell signature than organ-confined prostate cancer. Moreover, histological subtypes within prostate cancer metastases varied in their enrichment of the stem cell signature with small cell neuroendocrine carcinoma being the most stem cell-like. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common to all three signatures. These results suggest that the most aggressive variants of prostate cancer share a core transcriptional program with normal prostate basal stem cells. Transcriptional analysis of 10 uncultured prostatic basal and luminal populations from either the benign or malignant prostate tissue of 8 human prostate cancer patients by high-throughput RNA-seq
2016-06-01 | E-GEOD-82071 | biostudies-arrayexpress
Project description:Chronologically Modified Androgen Receptor in Recurrent Castration Resistant Prostate Cancer and its therapeutic targeting
| PRJNA682986 | ENA
Project description:The identification of biomarkers indicating the level of aggressiveness of prostate cancer (PCa) addresses an urgent clinical need to minimize the general over-treatment of patients with non-aggressive PCa, which account for the majority of PCa cases. In this study we combined N-glycopeptide isolation and SWATH-MS towards the molecular characterization of tumor malignancy and aggressiveness. Here, we isolated formerly N-linked glycopeptides from normal prostate (n=10), non-aggressive (n=22), aggressive (n=16) and metastatic PCa (n=25) tumor tissues and analyzed the samples by SWATH-MS, an emerging data independent mass spectrometric acquisition method that generates a single MS file containing fragment ion spectra of all ionized species of a sample. The resulting datasets were searched using a targeted data analysis strategy where a priori spectral reference library representing known N-glycosites of the human proteome was used to identify groups of signals in the SWATH-MS data. On-average we identified 1430 N-glycosites from each SWATH map of which 1057 were quantified across all samples. The 220 glycoproteins that showed significant quantitative changes associated diverse biological processes with the level of PCa aggressiveness and metastasis and indicated functional relationships with common PCa genomic mutations.
2014-04-23 | PXD000704 | Pride
Project description:Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. We performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy. We found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness. We further generated a 91-gene basal signature and applied it to gene expression datasets from patients with organ-confined or castration-resistant, metastatic prostate cancer. Metastatic prostate cancer was more enriched for the basal stem cell signature than organ-confined prostate cancer. Moreover, histological subtypes within prostate cancer metastases varied in their enrichment of the stem cell signature with small cell neuroendocrine carcinoma being the most stem cell-like. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common to all three signatures. These results suggest that the most aggressive variants of prostate cancer share a core transcriptional program with normal prostate basal stem cells.
2016-06-01 | GSE82071 | GEO
Project description:Current screening modalities for prostate cancer rely on serologic testing for PSA and transrectal biopsy; however, many prostate cancers behave indolently.Because aggressively growing tumors depend on oncogenic drivers, we hypothesized that we could identify early, but aggressive prostate cancer,by an imaging modality targeting Hsp90, a chaperone for many molecules involved in oncogenic signaling. Previously we observedgreater avidity ofa probe,consisting of a near infrared dye tethered to an Hsp90 inhibitor,for cancers with greatermetastatic potential. We now report that an Hsp90 inhibitor-linked near infrared dye with greater tissue penetration could detect prostate cancers in preclinical models and in a phase I human clinical trial. These data, demonstrating specific uptake into aggressive tumors, in conjunction with our prior observations on photodynamic therapy guided by Hsp90 expression support a theranostic approach todetect and treatearly aggressive prostatecancers.
2022-01-01 | GSE164865 | GEO