Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer

Urbinati, Giorgia; Ali, Hafız Muhammad; Rousseau, Quentin; Chapuis, Hubert; Desmaële, Didier; Couvreur, Patrick; Massaad-Massade, Liliane

doi:10.1371/journal.pone.0125277

Cited by 30 publications

(40 citation statements)

References 35 publications

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“…As previously described and discussed in our latest paper, 15 in vitro , the NPs siRNA TMPRSS2-ERG-SQ were unable to enter within the cells without a transfecting agent. But we already demonstrated that they are still active after bio-conjugation with squalene despite the chemical modifications.…”

Section: Discussionsupporting

confidence: 52%

Knocking Down TMPRSS2-ERG Fusion Oncogene by siRNA Could be an Alternative Treatment to Flutamide

Urbinati

Waziers

Slamić

et al. 2016

Molecular Therapy - Nucleic Acids

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Our purpose was to develop a new pharmacological approach for the treatment of prostate cancer (PCa), the most common neoplasia in men. Recently, we developed siRNA against the fusion oncogene TMPRSS2-ERG found in 50% of patients and showed an antitumoral activity in animal model. Herein, we want to compare or combine the developed siRNA to flutamide (FLU), one of the gold-standard treatment of PCa. Therefore, concomitant or subsequent association of FLU to siRNA TMPRSS2-ERG was performed in VCaP cells and in SCID mice bearing xenografted VCaP tumors. ERG, androgen receptor, cleaved-caspase-3 as well as phase 1 and 2 drug-metabolizing enzymes were investigated within tumors. We observed similar results in terms of TMPRSS2-ERG knock-down and cell viability impairment for all distinct schedules of administration. The association of siRNA TMPRSS2-ERG-squalene nanoparticles with flutamide displayed similar tumor growth inhibition as mice treated with siRNA TMPRSS2-ERG-squalene nanoparticles alone and was paralleled with modification of expression of ERG, androgen receptor, and cleaved-caspase-3. Phase 1 and 2 enzymes were essentially affected by FLU and reverted when combined with squalenoylated siRNA. In conclusion, these results confirm the therapeutic effectiveness of squalenoyl siRNA nanomedicine for PCa based on siRNA TMPRSS2-ERG.

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Section: Discussionsupporting

confidence: 52%

Knocking Down TMPRSS2-ERG Fusion Oncogene by siRNA Could be an Alternative Treatment to Flutamide

Urbinati

Waziers

Slamić

et al. 2016

Molecular Therapy - Nucleic Acids

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“…Several approaches to targeting ERG activity are currently in the early phases of development. Urbinati et al have used TE fusion junction targeted siRNAs, similar to our approach, delivered via conjugation to squalene and self‐organization into nanoparticles. Treatment with these nanoparticles resulted in decreased VCaP tumor growth in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that androgen deprivation alone will decrease TE fusion gene expression but TE re-expression is seen in castration-resistant PCa 36 due to a variety of alterations such as androgen receptor mutation Several approaches to targeting ERG activity are currently in the early phases of development. Urbinati et al 37 have used TE fusion junction targeted siRNAs, similar to our approach, delivered via conjugation to squalene and self-organization into nanoparticles. Treatment with these nanoparticles resulted in decreased VCaP tumor growth in vivo.…”

Section: Discussionmentioning

confidence: 99%

Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer

Shao

Kahraman

et al. 2019

The Prostate

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Background The TMPRSS2/ERG (TE) fusion gene is present in half of the prostate cancers (PCas). The TMPRSS2 and ERG junction of the fusion messenger RNA (mRNA) constitutes a cancer‐specific target. Although docetaxel‐based chemotherapy is the second line of therapy following development resistance to androgen ablation therapies, it is not curative. Therefore, the development of nontoxic novel monotherapies for targeting TE mRNA in PCa patients and for increasing the clinical efficacy of docetaxel treatment are needed. Methods We evaluated multiple approaches to enhance the delivery of TE small interfering RNA (siRNA) containing liposomes including PEGylation, topical treatment with nitroglycerin (NG) to increase permeability and retention, and three different PEG modifications: folate, RGD cyclic peptide, and a bFGF fibroblast growth factor receptor‐targeting peptide. The efficacy of the optimized TE siRNA liposome in combination with docetaxel was then evaluated in vivo with or without topical NG in vivo using a VCaP xenograft model. TE fusion protein knockdown in residual tumors was assessed using Western blotting and immunohistochemistry. Results In vivo therapeutic targeting of TE fusion gene by systemic delivery of RGD‐peptide‐coated liposomal siRNA nanovectors led to sustained target silencing, suppressed tumor growth in xenograft models and enhanced the efficacy of docetaxel chemotherapy. Simultaneous application of the vasodilator NG to the skin further increased tissue the delivery of siRNA and enhanced target knockdown. Conclusion TE‐targeted gene silencing therapy using liposomal nanovectors is a potential therapeutic strategy as a monotherapy and to enhance the efficacy of chemotherapy in patients with advanced PCa.

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“…Santoni et al indicated that fully understanding the role of TMPRSS2-ERG is important for individualised therapy in PCa patients (11). urbinati et al designed a kind of siRNA anti-TMPRSS2-ERG and successfully downregulated the expression of this fusion gene, and observably inhibited the proliferation of PCa cells (12). The above showed the potential and importance of TMPRSS2-ERG in PCa targeting treatment.…”

Section: Discussionmentioning

confidence: 99%

Identification of TMPRSS2-ERG mechanisms in prostate cancer invasiveness: Involvement of MMP-9 and plexin B1

Liu

Huang

et al. 2016

Oncology Reports

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The relationship of TMPRSS2-ERG fusion gene with matrix metalloproteinase-9 (MMP-9) and PLXNB1 (plexin B1) in regulation of prostate cancer (PCa) aggressiveness was investigated. Fluorescence in situ hybridization (FISH) assays, qRT-PCR and western blot analysis were employed to detect the expression of TMPRSS2-ERG fusion gene, ERG, MMP-9 and PLXNB1 of 135 human tissues, which included 55 metastatic PCa cases, 50 localized PCa cases and 30 BPH cases. Then using siRNA (anti-ERG, MMP-9 and PLXNB1, respectively) downregulation of the target gene of VCaP and PC-3 cells, MTT and Transwell were performed. The results showed that the positive rate of TMPRSS2-ERG fusion was 38.1% (40/105) in total PCa samples, 47.3% (26/55) of metastatic PCa, 28.0% (14/50) of localized PCa, while 0.0% (0/30) in BPH samples. The mRNA and protein expression of ERG, MMP-9 and PLXNB1 were higher in metastatic PCa (P<0.0001), and the mRNA expression of the three genes were positively correlated with TMPRSS2-ERG fusionin PCa group (P<0.0001). siRNA transfected PCa cells can effectively downregulate the target gene expression, and we identified that MMP-9 and PLXNB1 expression were all regulated by TMPRSS2-ERG fusion gene. While only PLXNB1 contributed to TMPRSS2-ERG mediated enhancements of VCaP cell migration and invasion. The results demonstrated that PLXNB1, but not MMP-9, was the target gene directly related to TMPRSS2-ERG in PCa cell migration and invasion.

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Antineoplastic Effects of siRNA against TMPRSS2-ERG Junction Oncogene in Prostate Cancer

Cited by 30 publications

References 35 publications

Knocking Down TMPRSS2-ERG Fusion Oncogene by siRNA Could be an Alternative Treatment to Flutamide

Knocking Down TMPRSS2-ERG Fusion Oncogene by siRNA Could be an Alternative Treatment to Flutamide

Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer

Identification of TMPRSS2-ERG mechanisms in prostate cancer invasiveness: Involvement of MMP-9 and plexin B1

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