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Reduction of Tumor Growth with RNA-Targeting Treatment of the NAB2-STAT6 Fusion Transcript in Solitary Fibrous Tumor
Yi Li1,2, John T Nguyen1,2, Manasvini Ammanamanchi1
1Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080, USA.
Abstract:
Solitary fibrous tumor (SFT) is a rare soft-tissue sarcoma. This nonhereditary cancer is the result of an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12, which fuses the activation domain of STAT6 with the repression domain of NAB2. Currently there is not an approved chemotherapy regimen for SFTs. The best response on available pharmaceuticals is a partial response or stable disease for several months. The purpose of this study is to investigate the potential of RNA-based therapies for the treatment of SFTs. Specifically, in vitro SFT cell models were engineered to harbor the characteristic NAB2-STAT6 fusion using the CRISPR/SpCas9 system. Cell migration as well as multiple cancer-related signaling pathways were increased in the engineered cells as compared to the fusion-absent parent cells. The SFT cell models were then used for evaluating the targeting efficacies of NAB2-STAT6 fusion-specific antisense oligonucleotides (ASOs) and CRISPR/CasRx systems. Our results showed that fusion specific ASO treatments caused a 58% reduction in expression of fusion transcripts and a 22% reduction in cell proliferation after 72 h in vitro. Similarly, the AAV2-mediated CRISPR/CasRx system led to a 59% reduction in fusion transcript expressions in vitro, and a 55% reduction in xenograft growth after 29 days ex vivo.
Insights
RNA-based therapies show promise for treating solitary fibrous tumors (SFTs). Antisense oligonucleotides and CRISPR/CasRx systems effectively reduced tumor growth and gene fusion expression in preclinical models.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Solitary fibrous tumor (SFT) is a rare soft-tissue sarcoma with no approved chemotherapy.
- SFTs arise from a specific NAB2-STAT6 gene fusion on chromosome 12.
- Current treatments offer limited efficacy, necessitating novel therapeutic approaches.
Purpose of the Study:
- To investigate RNA-based therapies targeting the NAB2-STAT6 gene fusion in SFTs.
- To develop and evaluate antisense oligonucleotides (ASOs) and CRISPR/CasRx systems for SFT treatment.
- To establish in vitro and ex vivo models for assessing therapeutic efficacy.
Main Methods:
- Engineered SFT cell models with the NAB2-STAT6 fusion using CRISPR/SpCas9.
- Evaluated NAB2-STAT6 fusion-specific antisense oligonucleotides (ASOs).
- Assessed AAV2-mediated CRISPR/CasRx system targeting the fusion transcript.
Main Results:
- ASO treatment reduced fusion transcripts by 58% and cell proliferation by 22% in vitro.
- CRISPR/CasRx system reduced fusion transcripts by 59% in vitro.
- CRISPR/CasRx system reduced xenograft growth by 55% ex vivo.
Conclusions:
- RNA-based therapies, including ASOs and CRISPR/CasRx, demonstrate significant potential for SFT treatment.
- Targeting the NAB2-STAT6 fusion is a viable strategy for SFT therapy.
- These preclinical findings support further development of RNA-based therapeutics for SFTs.
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