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Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown.

ABSTRACT: New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM⁺ tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2⁺ orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti-PD-1 checkpoint inhibition.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7936362 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown efficacy

Project description:New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here, we used EpCAM aptamer-linked small interfering RNAs (aptamer-siRNA chimeras (AsiCs)) to knockdown genes selectively in EpCAM+ tumors with the goal of making cancers more visible to the immune system to improve anti-tumor immunity. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2 and Parp1), phagocytosis and antigen presentation (Cd47), or cause tumor cell death (Mcl1). Using scRNA-seq, we showed that knocking down the four targets simutaeoulsy potently improved the anti-tumor immunity mediated T cells and macrophage/monocytes, demonstrating the immunostimulatory capacity of EpCAM-AsiCs.

2021-02-05 | GSE156214 | GEO

Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown efficacy

Project description:Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown efficacy

| PRJNA657057 | ENA

Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown efficacy_UPF2 knockdown in EpCAMhi MDA-MB-231 breast cancer cell lines

Project description:Knocking down Upf2, which encodes a protein that binds to prematurely terminated mRNAs to activate NMD, has been postulated to induce tumor cell expression of neoantigens to promote tumor recognition by T cells. To investigate whether Upf2 knockdown in breast cancer generates novel mRNA isoforms, we performed bulk RNA sequencing (RNA-seq) to compare an EpCAMhi MDA-MB-231 human breast cancer cell line transfected with noncoding control or UPF2 siRNA for 72 h. Results: 222 examples of differential exon usage (DEU) within 281 genes were identified. The number and diversity of DEUs suggest that UPF2 knockdown could have caused novel alternative splicing. To test this idea, UPF2 knockdown-related transcriptional diversity was deconvoluted to identify and estimate the abundance of transcript isoforms. 42 genes with potential differential isoform usage (DIU) were identified. Collectively, our data suggest that reducing NMD activity by UPF2 knockdown may induce expression of tumor neoantigens.

2021-02-05 | GSE156185 | GEO

Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown efficacy_UPF2 knockdown in EpCAMhi MDA-MB-231 breast cancer cell lines

Project description:Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown efficacy_UPF2 knockdown in EpCAMhi MDA-MB-231 breast cancer cell lines

| PRJNA657010 | ENA

Preclinical targeted therapy for retinoblastoma using EpCAM Aptamer siRNA chimeras

Project description:siRNAs have played a major role in cancer drug discovery, but their potential is hampered due to off-target effects. Thus, delivery systems like RNA aptamers have been used to enhance the specific delivery of these siRNAs to cancer stem cells. We report the efficacy of three different EpCAM aptamer siRNA chimeras, which were investigated both in vitro and in vivo for their ability to reduce cancer cell progression. Using these chimeras, we demonstrated specific gene knockdown in EpCAM positive cells which ultimately led to the apoptosis. To study the efficacy of these aptamer chimeras in vivo, retinoblastoma xenografts bearing NCC Rb C 51 cells were created for the first time. Systemic administration of these aptamer chimeras reduced tumour growth to about 50%. We further investigated the central Role of PLK1 in Cancer Progression and demonstrated the anti-cancer effects of targeted EpCAM siPLK1 approach. Using SILAC-Mass spectrometry analysis, we showed that silencing PLK 1 gene can lead to p53 mediated cell cycle arrest. Thus, we establish EpCAM-siRNA chimeras as potential markers for targeted anti-cancer applications, which paves a platform for efficient second line of therapies in addition to existing chemotherapy options.

2022-03-02 | PXD008221 | Pride

EpCAM aptamer mediated cancer cell specific delivery of EpCAM siRNA using polymeric nanocomplex.

Project description:BACKGROUND:Epithelial cell adhesion molecule (EpCAM) is overexpressed in solid tumors and regarded as a putative cancer stem cell marker. Here, we report that employing EpCAM aptamer (EpApt) and EpCAM siRNA (SiEp) dual approach, for the targeted delivery of siRNA to EpCAM positive cancer cells, efficiently inhibits cancer cell proliferation. RESULTS:Targeted delivery of siRNA using polyethyleneimine is one of the efficient methods for gene delivery, and thus, we developed a novel aptamer-PEI-siRNA nanocomplex for EpCAM targeting. PEI nanocomplex synthesized with EpCAM aptamer (EpApt) and EpCAM siRNA (SiEp) showed 198 nm diameter sized particles by dynamic light scattering, spherical shaped particles, of 151?±?11 nm size by TEM. The surface charge of the nanoparticles was -30.0 mV using zeta potential measurements. Gel retardation assay confirmed the PEI-EpApt-SiEp nanoparticles formation. The difference in size observed by DLS and TEM could be due to coating of aptamer and siRNA on PEI nanocore. Flow cytometry analysis revealed that PEI-EpApt-SiEp has superior binding to cancer cells compared to EpApt or scramble aptamer (ScrApt) or PEI-ScrApt-SiEp. PEI-EpApt-SiEp downregulated EpCAM and inhibited selectively the cell proliferation of MCF-7 and WERI-Rb1 cells. CONCLUSIONS:The PEI nanocomplex fabricated with EpApt and siEp was able to target EpCAM tumor cells, deliver the siRNA and silence the target gene. This nanocomplex exhibited decreased cell proliferation than the scrambled aptamer loaded nanocomplex in the EpCAM expressing cancer cells and may have potential for EpCAM targeting in vivo.

| S-EPMC4307906 | biostudies-literature

Gene delivery to breast cancer by incorporated EpCAM targeted DARPins into AAV2.

Project description:ObjectiveThe aim of this study is to evaluate an AAV vector that can selectively target breast cancer cells and to investigate its specificity and anti-tumor effects on breast cancer cells both in vitro and in vivo, offering a new therapeutic approach for the treatment of EpCAM-positive breast cancer.MethodsIn this study, a modified AAV2 viral vector was used, in which EpCAM-specific DARPin EC1 was fused to the VP2 protein of AAV2, creating a viral vector that can target breast cancer cells. The targeting ability and anti-tumor effects of this viral vector were evaluated through in vitro and in vivo experiments.ResultsThe experimental results showed that the AAV2MEC1 virus could specifically infect EpCAM-positive breast cancer cells and accurately deliver the suicide gene HSV-TK to tumor tissue in mice, significantly inhibiting tumor growth. Compared to the traditional AAV2 viral vector, the AAV2MEC1 virus exhibited reduced accumulation in liver tissue and had no impact on tumor growth.ConclusionThis study demonstrates that AAV2MEC1 is a gene delivery vector capable of targeting breast cancer cells and achieving selective targeting in mice. The findings offer a potential gene delivery system and strategies for gene therapy targeting EpCAM-positive breast cancer and other tumor types.

| S-EPMC10712102 | biostudies-literature

Systemically Targeted Cancer Immunotherapy and Gene Delivery using Transmorphic Particles.

Project description:Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limit clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno-associated virus DNA using coat proteins from a tumor-targeted bacteriophage (phage). We show that Transmorphic Phage/AAV (TPA) particles provide superior delivery of transgenes over current phage-derived vectors through greater diffusion across the extracellular space and improved intracellular trafficking. We used TPA to target the delivery of cytokine-encoding transgenes for interleukin-12 (IL12), and novel isoforms of IL15 and tumor necrosis factor alpha (TNFα) for tumor immunotherapy. Our results demonstrate selective and efficient gene delivery and immunotherapy against solid tumors in vivo, without harming healthy organs. Our transmorphic particle system provides a promising modality for safe and effective gene delivery, and cancer immunotherapies through cross-species complementation of two commonly used viruses

| S-SCDT-EMM-2021-15418P | biostudies-other

EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model.

Project description:Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology. Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells. Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours. Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours. This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.

| S-EPMC4672025 | biostudies-literature

EpCAM knockdown alters microRNA expression in retinoblastoma--functional implication of EpCAM regulated miRNA in tumor progression.

Project description:The co-ordinated regulation of oncogenes along with miRNAs play crucial role in carcinogenesis. In retinoblastoma (RB), several miRNAs are known to be differentially expressed. Epithelial cell adhesion molecule (EpCAM) gene is involved in many epithelial cancers including, retinoblastoma (RB) tumorigenesis. EpCAM silencing effectively reduces the oncogenic miR-17-92 cluster. In order to investigate whether EpCAM has wider effect as an inducer or silencer of miRNAs, we performed a global microRNA expression profile in EpCAM siRNA knockdown Y79 cells. MicroRNA profiling in EpCAM silenced Y79 cells showed seventy-three significantly up regulated and thirty-six down regulated miRNAs. A subset of these miRNAs was also validated in tumors. Functional studies on Y79 and WERI-Rb-1 cells transfected with antagomirs against two miRNAs of miR-181c and miR-130b showed striking changes in tumor cell properties in RB cells. Treatment with anti-miR-181c and miR-130b showed significant decrease in cell viability and cell invasion. Increase in caspase-3 level was noticed in antagomir transfected cell lines indicating the induction of apoptosis. Possible genes altered by EpCAM influenced microRNAs were predicted by bioinformatic tools. Many of these belong to pathways implicated in cancer. The study shows significant influence of EpCAM on global microRNA expression. EpCAM regulated miR-181c and miR-130b may play significant roles in RB progression. EpCAM based targeted therapies may reduce carcinogenesis through several miRNAs and target genes.

| S-EPMC4264963 | biostudies-literature

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