Solitary fibrous tumor (SFT) is a soft-tissue sarcoma occurring in adults and infants. This nonhereditary cancer results from an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12. Multiple studies suggest NAB2-STAT6 is the oncogenic driver, although the exact oncogenic mechanisms are unclear. Currently, there is no approved chemotherapy regimen for SFTs. Anti-angiogenic drugs developed to treat other cancers have been used on SFTs with limited success. None of the chemotherapies enable complete remission, with the best response being a partial response or stable disease for several months. Therefore, there is a critical need for systemic t...
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Solitary fibrous tumor (SFT) is a soft-tissue sarcoma occurring in adults and infants. This nonhereditary cancer results from an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12. Multiple studies suggest NAB2-STAT6 is the oncogenic driver, although the exact oncogenic mechanisms are unclear. Currently, there is no approved chemotherapy regimen for SFTs. Anti-angiogenic drugs developed to treat other cancers have been used on SFTs with limited success. None of the chemotherapies enable complete remission, with the best response being a partial response or stable disease for several months. Therefore, there is a critical need for systemic therapy. The proposed research aims to identify oncogenic mechanisms and develop long-term systemic treatment for SFT. Our team is well-positioned to accomplish this goal. We have built the first cell models of SFT, established several primary SFT cell lines, and acquired the first and only patient-derived xenograft (PDX) animal model from resected dedifferentiated SFT tissue samples. Furthermore, using these SFT cells and PDX models, in collaboration with Ionis Pharmaceuticals, we tested and showed that STAT6-targeting Antisense Oligonucleotides (ASOs) can efficiently downregulate the expression of the NAB2-STAT6 fusion transcripts in vitro and in vivo. Here, we propose the following aims: (a) evaluate the in vitro and in vivo efficacies and specificities of candidate ASOs; (b) investigate molecular mechanisms of SFTs using NAB2-STAT6 fusion- specific ASOs; and (c) evaluate the in vivo efficacies of candidate ASOs in combination with small-molecule chemotherapeutic agents against SFTs. Our project will have a major direct impact on solitary fibrous tumor therapeutics and, more broadly, other gene fusion-related cancer therapeutics.
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