Targeting Gene‐ViroTherapy for prostate cancer by DD3‐driven oncolytic virus‐harboring interleukin‐24 gene

Fan, Jianling; Wei, Na; Ding, Miao; Gu, Jin; Liu, Xin Ran; Li, Bing Hua; Qi, Rong; Huang, Wei; Li, Yu Hua; Xiong, Xiao Quan; Wang, Jian; Li, Run Sheng; Liu, Xin‐Yuan

doi:10.1002/ijc.25069

Cited by 28 publications

(21 citation statements)

References 29 publications

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“…Combining PCA3 with other new biomarkers further improves diagnostic and prognostic accuracy [6-9]. The specific activity of the PCA3 promoter in PCa cells may also be used as an additional strategy for targeted therapeutic approaches [10]. …”

Section: Introductionmentioning

confidence: 99%

PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

et al. 2012

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BackgroundPCA3 is a non-coding RNA (ncRNA) that is highly expressed in prostate cancer (PCa) cells, but its functional role is unknown. To investigate its putative function in PCa biology, we used gene expression knockdown by small interference RNA, and also analyzed its involvement in androgen receptor (AR) signaling.MethodsLNCaP and PC3 cells were used as in vitro models for these functional assays, and three different siRNA sequences were specifically designed to target PCA3 exon 4. Transfected cells were analyzed by real-time qRT-PCR and cell growth, viability, and apoptosis assays. Associations between PCA3 and the androgen-receptor (AR) signaling pathway were investigated by treating LNCaP cells with 100 nM dihydrotestosterone (DHT) and with its antagonist (flutamide), and analyzing the expression of some AR-modulated genes (TMPRSS2, NDRG1, GREB1, PSA, AR, FGF8, CdK1, CdK2 and PMEPA1). PCA3 expression levels were investigated in different cell compartments by using differential centrifugation and qRT-PCR.ResultsLNCaP siPCA3-transfected cells significantly inhibited cell growth and viability, and increased the proportion of cells in the sub G0/G1 phase of the cell cycle and the percentage of pyknotic nuclei, compared to those transfected with scramble siRNA (siSCr)-transfected cells. DHT-treated LNCaP cells induced a significant upregulation of PCA3 expression, which was reversed by flutamide. In siPCA3/LNCaP-transfected cells, the expression of AR target genes was downregulated compared to siSCr-transfected cells. The siPCA3 transfection also counteracted DHT stimulatory effects on the AR signaling cascade, significantly downregulating expression of the AR target gene. Analysis of PCA3 expression in different cell compartments provided evidence that the main functional roles of PCA3 occur in the nuclei and microsomal cell fractions.ConclusionsOur findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival, in part through modulating AR signaling, which may raise new possibilities of using PCA3 knockdown as an additional therapeutic strategy for PCa control.

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Section: Introductionmentioning

confidence: 99%

PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

et al. 2012

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“…More important, our results serve as a proof of principle to deploy alternative PCa-specific promoters that can distinguish malignant and benign disease. Several genes are upregulated at the transcriptional level specifically in PCa, including Differential Display Code 3 (DD3/PCA3), prostate- specific membrane antigen, and a-methylacyl-CoA racemase (32–34). Given the extensive track record of the TSTA method, it should be feasible to use the promoters of these genes to develop a parallel transcription-amplified imaging strategy to specifically image intraprostatic PCa foci and better guide treatments.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Imaging of Intraprostatic-Specific Gene Transcription by PET

Pouliot

Karanikolas²,

Johnson³

et al. 2011

J Nucl Med

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Better intraprostatic cancer imaging techniques are needed to guide clinicians in prostate cancer treatment decisions. Because many genes are specifically overexpressed in cancer cells, one strategy to improve prostate cancer detection is to image intraprostatic cancer-specific transcriptional activity. Because of the obstacles of weak cancer-or tissue-specific promoter activity and bladder clearance of many PET tracers, intraprostatic PET of gene transcriptional activity has not been previously reported. Methods: The two-step transcriptional amplification (TSTA) system that amplifies the prostate-specific antigen promoter activity was used for PET imaging of the reporter gene herpes simplex virus type-1 sr39 thymidine kinase (HSV1-sr39tk). The TSTA-sr39tk system was injected directly into prostates or prostatic tumors as a replication-incompetent adenovirus (AdTSTA-sr39tk) and imaged using PET. Results: AdTSTA-sr39tk was able to image prostate-specific antigen promoter transcriptional activity by 9-(4-18 F-fluoro-3-[hydroxymethyl]butyl)guanine PET, in both mouse and canine prostates in vivo. Ex vivo small-animal PET images, scintigraphic counts, and sr39tk expression analysis confirmed the specificity of the observed signal. Conclusion: Here, by combining the TSTA-amplified signal with a protocol for tracer administration, we show that in vivo PET detection of transcriptional activity is possible in both mouse and immunocompetent canine prostates. These results suggest that imaging applications using transcription-based tumor-specific promoters should be pursued to better visualize cancer foci that escape detection by conventional biopsies.

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“…In Ad-UI2, the TK gene is replaced by TRAIL 90. In the oncolytic mutant Ad.DD3-E1A, E1A expression and replication are regulated by the highly prostate-specific differential display code 3 ( DD3 ) promoter and express the secreted cytokine IL-24 or PTEN from the CMV promoter 91,92. The minimal DD3 promoter region of 214 nt was reported to have higher activity than the minimal PSA promoter/enhancer due to elimination of upstream silencer sequences.…”

Section: Optimizing Replication-selective Oncolytic Adenoviruses For mentioning

confidence: 99%

Oncolytic adenovirus-mediated therapy for prostate cancer

Sweeney

Halldén

2016

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Prostate cancer is a leading cause of cancer-related death and morbidity in men in the Western world. Tumor progression is dependent on functioning androgen receptor signaling, and initial administration of antiandrogens and hormone therapy (androgen-deprivation therapy) prevent growth and spread. Tumors frequently develop escape mechanisms to androgen-deprivation therapy and progress to castration-resistant late-stage metastatic disease that, in turn, inevitably leads to resistance to all current therapeutics, including chemotherapy. In spite of the recent development of more effective inhibitors of androgen–androgen receptor signaling such as enzalutamide and abiraterone, patient survival benefits are still limited. Oncolytic adenoviruses have proven efficacy in prostate cancer cells and cause regression of tumors in preclinical models of numerous drug-resistant cancers. Data from clinical trials demonstrate that adenoviral mutants have limited toxicity to normal tissues and are safe when administered to patients with various solid cancers, including prostate cancer. While efficacy in response to adenovirus administration alone is marginal, findings from early-phase trials targeting local-ized and metastatic prostate cancer suggest improved efficacy in combination with cytotoxic drugs and radiation therapy. Here, we review recent progress in the development of multimodal oncolytic adenoviruses as biological therapeutics to improve on tumor elimination in prostate cancer patients. These optimized mutants target cancer cells by several mechanisms including viral lysis and by expression of cytotoxic transgenes and immune-stimulatory factors that activate the host immune system to destroy both infected and noninfected prostate cancer cells. Additional modifications of the viral capsid proteins may support future systemic delivery of oncolytic adenoviruses.

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Targeting Gene‐ViroTherapy for prostate cancer by DD3‐driven oncolytic virus‐harboring interleukin‐24 gene

Cited by 28 publications

References 29 publications

PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

In Vivo Imaging of Intraprostatic-Specific Gene Transcription by PET

Oncolytic adenovirus-mediated therapy for prostate cancer

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