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: Patients with Neurofibromatosis type 1 (NF1) are at increased risk for developing malignant tumors of the connective tissue called soft-tissue sarcomas, including malignant peripheral nerve sheath tumor (MPNST), rhabdomyosarcoma (RMS), and undifferentiated pleomorphic sarcoma (UPS). These tumors are highly aggressive, with 5-year survival rates of 50-60%. We have developed novel mouse models of temporally and spatially restricted soft-tissue sarcoma in NF1flox/flox; Ink4a/Arf flox/flox mice. Following injection of an adenovirus expressing Cre recombinase (Ad-Cre), these mice develop MPNSTs after injection into the sciatic nerve or high-grade myogenic sarcomas (RMS/UPS) after injection into the muscle. During this research period, we have also developed an improved model that accelerates tumor formation while preserving the fidelity of this model. We are using these models as preclinical platforms to investigate the impact of the tumor microenvironment on sarcoma response to chemotherapy and to test novel approaches for treating NF1-mutant sarcomas. These studies may identify more efficacious treatments for patients with NF1-mutant sarcomas.

Testing Current and Developing Novel Therapies for NF1-Mutant Sarcomas in a Genetically Engineered Mouse Model