Abstract 1117: XenoSarc: Patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization
Authors: Wozniak Agnieszka , Van Renterghem Britt , Cornillie Jasmien , Wang Yannick , Lee Che-Jui , Wellens Jasmien , Vanleeuw Ulla , Nysen Madita , Hompes Daphne , Sinnaeve Friedl , Wafa Hazem , Topal Baki , Verbelen Tom , Debiec-Rychter Maria , Sciot Raf , Schöffski Patrick 
Published: September 2020

Background: STS constitutes a rare family of mesenchymal tumors with more than 70 subtypes classified by WHO (2013). The limited treatment options available for advanced STS underline the need for reliable preclinical models, especially from ultra-rare subtypes, to test novel therapeutic strategies.

Methods: A panel of PDX models was established by subcutaneous implantation of fresh tumor specimens in immunodeficient, athymic nude NMRI mice. Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of mice. At each passage tumor fragments were collected for histopathological and molecular characterization. A model was considered “established” after observing stable histological and molecular features for at least two passages. Furthermore, ex-mouse tumor tissue samples were stored, further characterized by immunocytology and flow cytometry and cultured to be used for in vitro drug testing.

Results: Between September 2011 and November 2019, 375 STS samples from 325 consenting patients treated at the University Hospitals, Leuven, Belgium have been transplanted. A total of 56 PDX models were established, maintaining the histopathological and molecular features of the original tumor. Detailed clinical information about the donor patient and tumor characteristics (including sensitivity to standard and experimental agents), is known for every model.

At present the XenoSarc platform includes ready to use models of dedifferentiated liposarcoma (11 models), gastrointestinal stromal tumor (8), myxofibrosarcoma (8), leiomyosarcoma (7), malignant peripheral nerve sheath tumor (3), synovial sarcoma (2), pulmonary artery intimal sarcoma (2), epithelioid hemangioendothelioma (1), mesenchymal chondrosarcoma (1), pleomorphic rhabdomyosarcoma (1), CIC-rearranged round cell sarcoma (1), myxoinflammatory fibroblastic sarcoma (1), rhabdomyosarcoma not otherwise specified (NOS) (1), telangiectatic extraskeletal osteosarcoma (1), extraskeletal osteosarcoma (1) and high-grade undifferentiated pleomorphic sarcoma (7). These models are well-characterized, including molecular information on copy number changes (by low-coverage whole genome sequencing), gene expression profile (by RNA-Seq) and targeted sequencing to detect mutations in genes involved in tumorigenesis. In addition, we have constructed tissue microarrays (TMA) from the xenografts which are used for target identification and model selection for preclinical studies. We are using the xenografts for in vivo testing of novel agents, including targeted and cytotoxic (pro-)drugs, and results already served as rationale for a number of prospective clinical trials. A total of 27 other xenografts are still in early stages of engraftment, not yet fulfilling our criteria of an “established” model.

Conclusion: The XenoSarc platform offers a lot of opportunities for studying the biology of a variety of important sarcoma subtypes including ultra-rare entities, and has proven efficiency for early drug screening in STS in preparation of clinical testing of novel compounds. The platform is well maintained and continuously expanded, and available to collaborators from academia and industry.

Citation Format: Agnieszka Wozniak, Britt Van Renterghem, Jasmien Cornillie, Yannick Wang, Che-Jui Lee, Jasmien Wellens, Ulla Vanleeuw, Madita Nysen, Daphne Hompes, Friedl Sinnaeve, Hazem Wafa, Baki Topal, Tom Verbelen, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. XenoSarc: Patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) and their histopathological and molecular characterization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1117.