American Association for Cancer Research
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10780432ccr122715-sup-fig2.pdf (7.91 MB)

Supplementary Figure 2 from Highly Specific Targeting of the TMPRSS2/ERG Fusion Gene Using Liposomal Nanovectors

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posted on 2023-03-31, 17:43 authored by Longjiang Shao, Ibrahim Tekedereli, Jianghua Wang, Erkan Yuca, Susan Tsang, Anil Sood, Gabriel Lopez-Berestein, Bulent Ozpolat, Michael Ittmann

PDF file - 8094K, Representative images of NFκB p65 phospho-Ser536 immunohistochemistry from VCaP xenograft tumors treated with scrambled control SiRNA or targeted SiRNAs (Si8 or Si14). Original magnification: 400X.

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ARTICLE ABSTRACT

Purpose: The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in prostate cancer cells. The junction of theTMPRSS2- and ERG-derived portions of the fusion mRNA constitutes a cancer-specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low-toxicity treatment for prostate cancer.Experimental Design: We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (type III or type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of prostate cancer cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms.Results: The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed.Conclusions: Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with prostate cancer. Clin Cancer Res; 18(24); 6648–57. ©2012 AACR.

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