(P 198) XENOSARC: A PANEL OF PATIENT-DERIVED XENOGRAFT (PDX) MODELS OF SOFT TISSUE SARCOMA FOR PRECLINICAL DRUG EVALUATION

Objective: Soft tissue sarcoma (STS) constitutes a family of rare mesenchymal tumors with more than 70 subtypes described. The limited treatment options available for advanced STS patients underline the need for reliable preclinical models to test new therapeutic approaches.

Methods: We established a panel of PDX models (XenoSarc) by subcutaneous implantation of fresh tumor fragments in athymic mice (nu/nu NRMI). Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of animals. At each passage tumor specimens were collected for histopathological and molecular characterization.

Results: In an ongoing effort 510 STS samples from 429 consenting patients treated at the University Hospitals, Leuven (Belgium) have been transplanted. A total of 73 PDX models from 17 STS subtypes have been established, meaning they have stable morphological, immunohistochemical and genetic characteristics over at least 2 passages. The PDX platform includes more common STS subtypes such as myxofibrosarcoma (n=12 models), dedifferentiated liposarcoma (12), gastrointestinal stromal tumors (11), and leiomyosarcoma (9), as well as models from ultra-rare subtypes, e.g. pulmonary intimal sarcoma, extraskeletal osteosarcoma, mesenchymal chondrosarcoma, myxoinflammatory fibroblastic sarcoma and others. Important details about the donor patient and tumor characteristics, including sensitivity to the standard treatments, are known for every model. The models are well-characterized, with availability of molecular information on genomic profile (by low-coverage whole genome sequencing), and expression profile (by RNA sequencing). Xenografts are accompanied by ready to use tissue microarrays (TMA) from the models, which can be exploited for target identification and model selection for preclinical studies. Ex-mouse material has also been used to establish primary cell cultures and 3D organoids for in vitro screening purposes.

Conclusion: The XenoSarc platform offers opportunities for studying the biology of various sarcoma subtypes including ultra-rare entities and was found to be a very reliable tool for early drug screening in STS in preparation of clinical testing of novel compounds. The platform is available for collaborative preclinical projects with academic and industrial partners.