Soft-tissue sarcoma (STS) is a recalcitrant group of malignancies with over 50 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 25 years.1-12 PDOX models of colon cancer,1,13 pancreatic cancer,2 lung cancer,3 breast cancer,5 ovarian cancer,4 stomach cancer,6 cervical cancer11 and mesothelioma9 were previously established. In these models, the orthotopic site was determined and metastasis resulted that matched the donor patient.6,11 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 25 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 Ewings 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: 1) 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. 2) 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.
Public Health Relevance Statement: 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 patients 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 25 years.1-12 PDOX models of colon cancer,1,13 pancreatic cancer,2 lung cancer,3 breast cancer,5 ovarian cancer,4 stomach cancer,6 cervical cancer11 and mesothelioma9 were previously established. In these models, the orthotopic transplantation site was determined and metastasis resulted that matched the donor patient.6,11 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 25 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 Ewings 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.
Project Terms: abstracting; Anatomy; Behavior; cancer type; Cervical; chemotherapy; Chondrosarcoma; Clinical; clinically relevant; Collaborations; Collection; Colon Carcinoma; Disease; Disease Progression; Distant Metastasis; drug discovery; Follicular Dendritic Cell Sarcoma; Future; Goals; Grant; Histologic; Implant; International; Laboratories; Legal patent; leiomyosarcoma; Limb structure; liposarcoma; malignant breast neoplasm; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant Neoplasms; malignant stomach neoplasm; Modeling; mouse model; Mus; Muscle; Myxoid Malignant Fibrous Histiocytoma; Names; Neoplasm Metastasis; Neoplasm Transplantation; novel therapeutics; Nude Mice; Operative Surgical Procedures; Outcome; Patient Representative; Patients; Peritoneum; personalized medicine; Phase; Primary Neoplasm; Procedures; programs; Recurrence; Research; response; Retroperitoneal Space; sarcoma; Series; Site; skeletal; Small Business Innovation Research Grant; Soft tissue sarcoma; Specific qualifier value; success; synovial sarcoma; Technology; Therapeutic; Thoracic cavity structure; Transplantation; tumor; tumor growth; Undifferentiated; Xenograft Model; Xenograft procedure
