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Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58975 | GEO | 2014/07/15

SECONDARY ACCESSION(S): PRJNA254030

REPOSITORIES: GEO

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Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer.

Project description:Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.

| S-EPMC5443258 | biostudies-literature

Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer (expression)

Project description:Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. The most prevalent consensus peptide series matched the tumor suppressor Deleted in Liver Cancer 1 (DLC1). ERG inhibitory peptides and derived peptidomimetics (EIPs) bound with high affinity and specificity leading to proteolytic degradation of ERG. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other cancers.

2014-07-15 | GSE58940 | GEO

Development of peptidomimetic inhibitors of the ERG transcription factor in prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-07-15 | E-GEOD-58975 | biostudies-arrayexpress

Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer

Project description:Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer

| PRJNA254030 | ENA

Development of peptidomimetic inhibitors of the ERG transcription factor in prostate cancer (expression)

Project description:Transcription factors play a key role in the development of a number of cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the ETS transcription factor ERG is recurrently rearranged and likely plays a critical role in prostate oncogenesis. Here we identified a series of peptides from a phage-display library that interact specifically with the DNA binding domain of ERG. The interactive interface was mapped to 9-residues in the 3rd -helix of the ETS domain that is critical for ERG transcriptional activity. The peptides were found to efficiently disrupt ERG-mediated protein-protein interactions, transcription, DNA damage, and cell invasion, as well as attenuate ERG recruitment to target gene loci. Furthermore, a retroinverso peptidomimetic version of the peptide sequence suppressed tumor growth, intravasation, and metastasis in vivo. Taken together, our results demonstrate that transcription factors have specific residues important for protein-protein interactions and disrupting those critical interactions may be an effective therapeutic strategy. Prostate cancer cell line VCaP were treated with 10ÂµM of RI-EIP1 or RI-muEIP1 for 48 hr

2014-07-15 | E-GEOD-58940 | biostudies-arrayexpress

Development of peptidomimetic inhibitors of the ERG transcription factor in prostate cancer (ChIP-seq)

Project description:Transcription factors play a key role in the development of a number of cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the ETS transcription factor ERG is recurrently rearranged and likely plays a critical role in prostate oncogenesis. Here we identified a series of peptides from a phage-display library that interact specifically with the DNA binding domain of ERG. The interactive interface was mapped to 9-residues in the 3rd helix of the ETS domain that is critical for ERG transcriptional activity. The peptides were found to efficiently disrupt ERG-mediated protein-protein interactions, transcription, DNA damage, and cell invasion, as well as attenuate ERG recruitment to target gene loci. Furthermore, a retroinverso peptidomimetic version of the peptide sequence suppressed tumor growth, intravasation, and metastasis in vivo. Taken together, our results demonstrate that transcription factors have specific residues important for protein-protein interactions and disrupting those critical interactions may be an effective therapeutic strategy. Examination of ERG in VCaP cells with respect to peptidomimetics treatment

2014-07-15 | E-GEOD-58939 | biostudies-arrayexpress

Development of peptidomimetic inhibitors of the ERG transcription factor in prostate cancer (ChIP-seq)

Project description:Transcription factors play a key role in the development of a number of cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the ETS transcription factor ERG is recurrently rearranged and likely plays a critical role in prostate oncogenesis. Here we identified a series of peptides from a phage-display library that interact specifically with the DNA binding domain of ERG. The interactive interface was mapped to 9-residues in the 3rd helix of the ETS domain that is critical for ERG transcriptional activity. The peptides were found to efficiently disrupt ERG-mediated protein-protein interactions, transcription, DNA damage, and cell invasion, as well as attenuate ERG recruitment to target gene loci. Furthermore, a retroinverso peptidomimetic version of the peptide sequence suppressed tumor growth, intravasation, and metastasis in vivo. Taken together, our results demonstrate that transcription factors have specific residues important for protein-protein interactions and disrupting those critical interactions may be an effective therapeutic strategy.

2014-07-15 | GSE58939 | GEO

An Integrated Network of Androgen Receptor and TMPRSS2-ERG Gene Fusion in Prostate Cancer Progression

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2010-05-18 | E-GEOD-14097 | biostudies-arrayexpress

Development of a peptide-based vaccine targeting TMPRSS2:ERG fusion-positive prostate cancer.

Project description:Identification of novel vaccine targets is critical for the design and advancement of prostate cancer (PCa) immunotherapy. Ideal targets are proteins that are abundant in prostate tumors while absent in extra-prostatic tissues. The fusion of the androgen-regulated TMPRSS2 gene with the ETS transcription factor ERG occurs in approximately 50 % of prostate cancer cases and results in aberrant ERG expression. Because expression of ERG is very low in peripheral tissue, we evaluated the suitability of this protein as an antigen target in PCa vaccines. ERG-derived HLA-A*0201-restricted immunogenic epitopes were identified through a 3-step strategy that included in silico, in vitro, and in vivo validation. Algorithms were used to predict potential HLA-A*0201-binding epitopes. High-scoring epitopes were tested for binding to HLA-A*0201 using the T2-based stabilization assay in vitro. Five peptides were found to bind HLA-A*0201 and were subsequently tested for immunogenicity in humanized, HLA-A*0201 transgenic mice. The in vivo screening identified three immunogenic peptides. One of these peptides, ERG295, overcame peripheral tolerance in HLA-A*0201 mice that expressed prostate-restricted ERG. Also, this peptide induced an antigen-specific response against ERG-expressing human prostate tumor cells. Finally, tetramer assay showed detectable and responsive ERG295-specific cytotoxic lymphocytes in peripheral blood of HLA-A*0201(+) prostate cancer patients. Detection of ERG-specific CTLs in both mice and the blood of prostate cancer patients indicates that ERG-specific tolerance can be overcome. Additionally, these data suggest that ERG is a suitable target antigen for PCa immunotherapy.

| S-EPMC3864132 | biostudies-literature

An Integrated Network of Androgen Receptor and TMPRSS2-ERG Gene Fusion in Prostate Cancer Progression

Project description:This SuperSeries is composed of the SubSeries listed below.

2010-05-18 | GSE14097 | GEO