309dcaf3-072e-401f-be8a-8aa2129b9cf7 - samples
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ABSTRACT:
PROVIDER: EGAD00001008462 | EGA |
REPOSITORIES: EGA
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Project description:Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration resistant prostate cancer (mCRPC) during treatment. Patients and Methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation states of genes previously implicated in prostate cancer progression were observed, and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression (TTP). Importantly, we also report that markers associated with a highly aggressive form of the disease, Neuroendocrine-CRPC, were associated with a faster TTP. Conclusion: Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.
2020-09-04 | GSE152631 | GEO
Project description:Achieved biospecimens annotated with patient clinical characteristics are unique resources for translational research. However, RNA extracted from the achieved tissues is often degraded. RNA degradation can have a significant impact on the measure of transcript abundance that can lead to an increase rate of erroneous differentially expressed genes. Here, we are presenting the transcript integrity number (TIN) algorithm to measure the RNA degradation at transcript level. When applied to RNA-seq datasets generated from human brain Glioblastome cell line, human peripheral blood mononuclear cells, and metastatic castration resistant prostate cancer (mCRPC) clinical tissues, TIN provided a more reliable and more sensitive measure of RNA degradation than RIN, as demonstrated by much higher concordance with the RNA fragment size estimated from read pairs. More importantly, when comparing 10 mCRPC samples with lower RNA quality to another 10 samples with higher RNA quality, we demonstrated that calibrating gene quantification with TIN scores could mitigate RNA degradation effects and greatly improve gene expression analysis. The detected differentially expressed genes before TIN correction were predominantly ribosomal genes. However, when we adjusted gene quantifications with the corresponding TIN scores, we found differentially expressed genes were highly enriched in prostate cancer specific pathways. When further evaluating the performance of TIN correction using synthetic spike-in transcripts with predetermined abundance in RNA-seq data generated from Sequencing Control Consortium (SEQC), we found TIN adjustment had a better control of false positives and false negatives (sensitivity = 0.89, specificity = 0.91), as compared to gene expression analysis results without TIN correction (sensitivity =0.98, specificity = 0.50). RNA sequencing of 20 bone-metastatic castration resistant prostate cancer (mCRPC) using Illumina HiSeq 2500. Out of 20 mCRPC samples, 10 samples have relative low RNA integrity and another 10 samples have relative higher RNA integrity as measured by Agilent RIN score.
2016-02-19 | E-GEOD-70285 | biostudies-arrayexpress
Project description:The widespread and long-term use of potent therapies designed to repress androgen receptor (AR) signaling is changing the molecular and phenotypic landscapes of prostate cancer. We conducted molecular profiling of metastatic castration-resistant prostate cancer (mCRPC) patient specimens and patient-derived xenograft models and identified five distinct mCRPC phenotypes. Herein, we characterize an AR-low phenotype that has low AR expression with concomitant decreases in a subset of AR regulated genes, and an amphicrine phenotype that has both AR and neuroendocrine activity in the same cell. Furthermore, our data highlight an emerging squamous cell mCRPC phenotype.
2019-07-17 | GSE126078 | GEO
Project description:Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
2017-01-10 | GSE80685 | GEO
Project description:With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Additionally, we have detected upregulated expression of MET and RET transcripts in SCNPC metastases relative to adenocarcinoma. Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits MET, RET and VEGFR2, on SCNPC patient-derived xenografts (PDX) in vivo. Surveillance of SU2C and University of Washington rapid autopsy mCRPC cohorts through RNA-Seq revealed that increased MET expression significantly correlated with loss of AR expression and activity. In vitro treatment of SCNPC PDX cells with AMG 337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability in LuCaP 93, but not in LuCaP 173.1. Notably, tumor volume was significantly decreased (p<0.001) with cabozantinib treatment in SCID mice bearing LuCaP 93 and LuCaP 173.1 tumors. Tissue analysis indicated that tumor cell proliferation was not inhibited by cabozantinib, but that cabozantinib decreased microvessel density (CD31) in LuCaP 93 (p<0.001) and LuCaP 173.1 (p<0.01) tumors. RNA-Seq and gene set enrichment analysis determined that hypoxia and glycolysis pathways were increased in cabozantinib treated tumors relative to control tumors. Thus, cabozantinib inhibited tumor growth in MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumors in vivo and this activity was independent of MET or RET expression in LuCaP 173.1. Our data suggest that the most likely mechanism of tumor growth suppression is through disruption of the stromal architecture and cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.
2021-01-27 | GSE148538 | GEO
Project description:Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) usually develops through cellular plasticity. We recently characterized two mCRPC phenotypes with NE features; Androgen receptor (AR)-positive, NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogate the RE-1 silencing transcription factor (REST) pathway in mCRPC and demonstrate that SRRM3 has analogous functions to SRRM4 and mediates NE differentiation through alternative splicing of REST. We scrutinize transcriptome datasets across species and tumor types and discover that SRRM3 and SRRM4 expression define molecular phenotypes in AMPC and SCNPC. Notably, we characterize two AMPC phenotypes driven by either REST attenuation or ASCL1 activity and three SCNPC phenotypes with progressive activation of neuronal transcription factor programs. Together, our data provides a biological framework for classifying NE phenotypes in mCRPC that could be useful for future therapeutic development and precision medicine applications.
2021-07-14 | GSE158598 | GEO
Project description:Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) usually develops through cellular plasticity. We recently characterized two mCRPC phenotypes with NE features; Androgen receptor (AR)-positive, NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogate the RE-1 silencing transcription factor (REST) pathway in mCRPC and demonstrate that SRRM3 has analogous functions to SRRM4 and mediates NE differentiation through alternative splicing of REST. We scrutinize transcriptome datasets across species and tumor types and discover that SRRM3 and SRRM4 expression define molecular phenotypes in AMPC and SCNPC. Notably, we characterize two AMPC phenotypes driven by either REST attenuation or ASCL1 activity and three SCNPC phenotypes with progressive activation of neuronal transcription factor programs. Together, our data provides a biological framework for classifying NE phenotypes in mCRPC that could be useful for future therapeutic development and precision medicine applications.
2021-07-14 | GSE158593 | GEO
Project description:This is a first-in-human, multi-center, open-label clinical study with separate dose escalation (Phase 1) and expansion (Phase 2) stages to assess preliminary safety, tolerability, and efficacy of the second generation oral XPO1 inhibitor KPT-8602 in participants with relapsed/refractory multiple myeloma (MM), metastatic colorectal cancer (mCRC), metastatic castration resistant prostate cancer (mCRPC), higher risk myelodysplastic syndrome (HRMDS), acute myeloid leukemia (AML) and newly diagnosed intermediate/high-risk MDS.
Dose escalation and dose expansion may be included for all parts of the study as determined by ongoing study results.
| 2205768 | ecrin-mdr-crc
Project description:Higher expression levels of DLX1 has been associated with primary and metastatic prostate tumor. DLX1 along with HOXC6 is well-established diagnostic biomarker for the early detection of prostate cancer (PCa). However, the mechanism involved in DLX1 up-regulation and functional significance in metastatic castration-resistant prostate cancer (mCRPC) progression remains unexplored. Here, we identified that DLX1 serves as an oncogene thereby regulating several oncogenic properties associated with PCa progression.
2021-07-30 | GSE138738 | GEO
Project description:We identified 27 long noncoding RNAs with differential expression (DE-lncRNAs) between prostate cancer metastases and corresponding primary tumors, suggesting that they are metastatic castration resistant prostate cancer (mCRPC)-specific lncRNAs. To assess androgen regulation of the DE-lncRNAs, we investigated their expression in LNCaP and VCaP cells induced with dihydrotestosterone (DHT) as well as in androgen receptor (AR)-silenced cells by using RNA-sequencing.
2023-05-04 | GSE223024 | GEO