Solitary fibrous tumor (SFT) is a soft-tissue sarcoma occurring in adults and infants. This non-hereditary cancer results from an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12, which combines the activation domain of STAT6 with the repression domain of NAB2. Anatomically, these blood vessel-derived tumors can occur anywhere; however, most occur within the meninges of the head. Intracranial SFTs have a high rate of local recurrence (65%), metastases (33%), and overall survival of less than 10 years. Either surgery or radiation is the first line of treatment against this cancer; however, for many, this becomes challenging as the cancer can travel to inopera...
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Solitary fibrous tumor (SFT) is a soft-tissue sarcoma occurring in adults and infants. This non-hereditary cancer results from an environmental intrachromosomal gene fusion between NAB2 and STAT6 on chromosome 12, which combines the activation domain of STAT6 with the repression domain of NAB2. Anatomically, these blood vessel-derived tumors can occur anywhere; however, most occur within the meninges of the head. Intracranial SFTs have a high rate of local recurrence (65%), metastases (33%), and overall survival of less than 10 years. Either surgery or radiation is the first line of treatment against this cancer; however, for many, this becomes challenging as the cancer can travel to inoperable areas or recur in locations already irradiated. Therefore, there is a need for systemic therapy. 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 enables complete remission, with the best response being a partial response or stable disease for several months. The average survival of patients on the current chemotherapies is 2 years. Major Histocompatibility Complex (MHC) class I expression is often altered in cancerous tissues. Here, we hypothesize that HPC-specific NAB2-STAT6 gene fusion peptides are presented by MHC I and can be exploited for immunotherapy. More specifically, we propose two Aims: (I) to identify NAB2-STAT6 fusion-derived HLA I-binding peptides in primary SFT cells and generate corresponding single-chain Fv (scFv) or VHH (llama) single-domain antibodies; and (II) to explore the effects of NAB2-STAT6 fusion types and HLA allele types on the presentation patterns of NAB2-STAT6 fusion-derived HLA I-binding peptides. We envision that our project will not only help establish a novel therapeutic paradigm for SFT but also inspire novel personalized MHC-based immunotherapy approaches for other gene fusion-driven cancers.
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