Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy

Velasco, Marco A. De; Kura, Yurie; Sakai, Kazuko; Hatanaka, Yuji; Davies, Barry R.; Campbell, Hayley; Klein, Stéphanie; Kim, Youngsoo; MacLeod, A. Robert; Sugimoto, Koichi; Yoshikawa, Kazuhiro; Nishio, Kazuto; Uemura, Hirotsugu

doi:10.1172/jci.insight.122688

Cited by 28 publications

(26 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Promising therapies include the modulation of AR signaling, which can be modified in different ways, such as with ASC-J9, an enhancer of AR degradation that suppressed bladder cancer in pre-clinical trials (only clinical trials for acne are currently registered) and AZD 5312, an AR antisense oligonucleotide that has already completed phase I clinical trials for solid tumors [ 120 , 121 , 122 , 123 ].…”

Section: Bladder Cancer Therapiesmentioning

confidence: 99%

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

et al. 2021

View full text Add to dashboard Cite

Bladder cancer (urothelial carcinoma) is one of the most frequently diagnosed neoplasms, with an estimated half a million new cases and 200,000 deaths per year worldwide. This pathology mainly affects men. Men have a higher risk (4:1) of developing bladder cancer than women. Cigarette smoking and exposure to chemicals such as aromatic amines, and aniline dyes have been established as risk factors for bladder cancer and may contribute to the sex disparity. Male internal genitalia, including the urothelium and prostate, are derived from urothelial sinus endoderm; both tissues express the androgen receptor (AR). Several investigations have shown evidence that the AR plays an important role in the initiation and development of different types of cancer including bladder cancer. In this article, we summarize the available data that help to explain the role of the AR in the development and progression of bladder cancer, as well as the therapies used for its treatment.

show abstract

Section: Bladder Cancer Therapiesmentioning

confidence: 99%

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…ASOs synthesized by next-generation chemistry have increased binding affinity, nuclease resistance, and enhanced biostability ( Seth et al., 2009 ; Murray et al., 2012 ). The efficacy of ASO-based therapy in clinics has already been demonstrated in several cases, including neurodegenerative diseases, metabolic syndrome, and cancer ( Linnane et al., 2019 ; Hong et al., 2015 ; De Velasco et al., 2019 ; Xiao et al., 2018 ; Xu et al., 2019 ; Kim et al., 2019a , 2019b ; Arun et al., 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Targeting Smyd3 by next-generation antisense oligonucleotides suppresses liver tumor growth

et al. 2021

Self Cite

View full text Add to dashboard Cite

Summary The oncogenic function of suppressor of variegation, enhancer of zeste and MYeloid-Nervy-DEAF1-domain family methyltransferase Smyd3 has been implicated in various malignancies, including hepatocellular carcinoma (HCC). Here, we show that targeting Smyd3 by next-generation antisense oligonucleotides (Smyd3-ASO) is an efficient approach to modulate its mRNA levels in vivo and to halt the growth of already initiated liver tumors. Smyd3-ASO treatment dramatically decreased tumor burden in a mouse model of chemically induced HCC and negatively affected the growth rates, migration, oncosphere formation, and xenograft growth capacity of a panel of human hepatic cancer cell lines. Smyd3-ASOs prevented the activation of oncofetal genes and the development of cancer-specific gene expression program. The results point to a mechanism by which Smyd3-ASO treatment blocks cellular de-differentiation, a hallmark feature of HCC development, and, as a result, it inhibits the expansion of hepatic cancer stem cells, a population that has been presumed to resist chemotherapy.

show abstract

“…Several antisense oligonucleotides (ASOs) targeting the AR have also been used with promising results, including one that is currently in a phase I clinical trial. 28 , 29 Nonetheless, the analysis of 914 samples from five independent studies indicated that both RNaseH2A and RNaseH2B are depleted in PCa. 30 Downregulation of RNaseH2B, which is required for ASO activity, could present a significant challenge to the use of ASOs.…”

Section: Resultsmentioning

confidence: 99%

“… 28 , 29 , 40 Some excellent work using a PCa mouse model has been performed by Yamamoto et al. 28 and De Velasco et al., 29 who developed an effective AR ASO (IONIS-AR-2.5Rx). This ASO is currently being tested in a phase I PCa clinical trial in combination with enzalutamide.…”

Section: Discussionmentioning

confidence: 99%

A Multifunctional LNA Oligonucleotide-Based Strategy Blocks AR Expression and Transactivation Activity in PCa Cells

Castanotto

Zhang

Rüger

et al. 2021

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

The androgen receptor (AR) plays a critical role in the development of prostate cancer (PCa) through the activation of androgen-induced cellular proliferation genes. Thus, blocking AR-mediated transcriptional activation is expected to inhibit the growth and spread of PCa. Using tailor-made splice-switching locked nucleic acid (LNA) oligonucleotides (SSOs), we successfully redirected splicing of the AR precursor (pre-)mRNA and destabilized the transcripts via the introduction of premature stop codons. Furthermore, the SSOs simultaneously favored production of the AR45 mRNA in lieu of the full-length AR. AR45 is an AR isoform that can attenuate the activity of both full-length and oncogenic forms of AR by binding to their common N-terminal domain (NTD), thereby blocking their transactivation potential. A large screen was subsequently used to identify individual SSOs that could best perform this dual function. The selected SSOs powerfully silence AR expression and modulate the expression of AR-responsive cellular genes. This bi-functional strategy that uses a single therapeutic molecule can be the basis for novel PCa treatments. It might also be customized to other types of therapies that require the silencing of one gene and the simultaneous expression of a different isoform.

show abstract

Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy

Cited by 28 publications

References 68 publications

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

Targeting Smyd3 by next-generation antisense oligonucleotides suppresses liver tumor growth

A Multifunctional LNA Oligonucleotide-Based Strategy Blocks AR Expression and Transactivation Activity in PCa Cells

Contact Info

Product

Resources

About