Establishment of a patient like mouse models of soft tissue sarcoma sub types

Project Summary Abstract Soft tissue sarcoma STS is a recalcitrant group of malignancies with over distinct histologic subtypes Patient derived mouse models of the representative STS subtypes that recapitulates disease progression and metastasis optimize the potential for individualizing STS therapy and for discovery of more effective therapeutics Our laboratory pioneered patient derived orthotopic xenograft PDOX mouse models and has been developing PDOX models of major cancer types for more than years PDOX models of colon cancer pancreatic cancer lung cancer breast cancer ovarian cancer stomach cancer cervical cancer and mesothelioma were previously established In these models the orthotopic site was determined and metastasis resulted that matched the donor patient For the past year we have focused on establishing a series of mouse models of soft tissue sarcoma STS and have established a series of patient derived STS that represent the most common histologic subtypes including liposarcoma leiomyosarcoma myxofibrosarcoma synovial sarcoma and undifferentiated pleomorphic sarcoma sarcoma not otherwise specified NOS In addition we have established several of the more uncommon STS subtypes including follicular dendritic cell sarcoma extra osseous Ewing s soft tissue sarcoma and extra skeletal chondrosarcoma The goal of the present application is to determine the correct orthotopic transplantation site for the STS types in order to obtain reliable primary tumor growth and both regional and distant metastasis similar to that seen in patients The specific aims are as follows Transplant a series of established STS tumors into different anatomic sites in nude mice including extremity muscle retroperitoneum peritoneum and the thoracic cavity depending on the histotype and site of origin or recurrence Evaluate the clinical similarity of the outcome of transplant site with respect to primary tumor growth and metastasis Deliverables The present application will develop patient like models of STS sub types enabling future personalized therapy and new drug discovery for this recalcitrant disease Project Narrative Soft tissue sarcoma STS is a recalcitrant tumor with distinct subtypes Clinically representative patient derived mouse models of the STS subtypes that metastasize similar to the patient would offer potential for individualizing STS therapy and for discovery of more effective therapeutics Our laboratory has shown that the site of transplantation of patient tumors in mice determine whether the tumor can replicate its behavior in the patient Implanting a patient s tumor subcutaneously although a simple procedure does not allow the tumor to metastasize In contrast transplanting the tumor orthotopically literally correct place enables the tumor to replicate the behavior in the patient Our laboratory pioneered patient derived orthotopic xenograft literally outside graft or grant from another species PDOX mouse models and has been developing PDOX models of major cancer types for more than years PDOX models of colon cancer pancreatic cancer lung cancer breast cancer ovarian cancer stomach cancer cervical cancer and mesothelioma were previously established In these models the orthotopic transplantation site was determined and metastasis resulted that matched the donor patient For the past year we have focused on establishing a series of mouse models of soft tissue sarcoma STS and have established a series of patient derived STS that represent the most common histologic subtypes including liposarcoma leiomyosarcoma myxofibrosarcoma synovial sarcoma and undifferentiated pleomorphic sarcoma sarcoma not otherwise specified NOS In addition we have established several of the more uncommon STS subtypes including follicular dendritic cell sarcoma extra osseous Ewing s soft tissue sarcoma and extra skeletal chondrosarcoma The goal of the present application is to determine the correct orthotopic transplantation site for the STS types in order to obtain reliable primary tumor growth and both regional and distant metastasis similar to that seen in patients These models will enable future personalized therapy of STS patients as well as discovery of more effective therapeutics of this recalcitrant disease