Over the past decade, the development of new targeted therapeutics directed against specific molecular pathways involved in tumor cell proliferation and survival has allowed an essential improvement in carcinoma treatment. Unfortunately, the scenario is different for sarcomas, a group of malignant neoplasms originating from mesenchymal cells, for which the main therapeutic approach still consists in the combination of surgery, chemotherapy, and radiation therapy. The lack of innovative approaches in sarcoma treatment stems from the high degree of heterogeneity of this tumor type, with more that 70 different histopathological subtypes, and the limited knowledge of the molecular drivers of tumor development and progression. Currently, molecular therapies are available mainly for the treatment of gastrointestinal stromal tumor, a soft-tissue malignancy characterized by an activating mutation of the tyrosine kinase KIT. Since the first application of this approach, a strong effort has been made to understand sarcoma molecular alterations that can be potential targets for therapy. The low incidence combined with the high level of histopathological heterogeneity makes the development of clinical trials for sarcomas very challenging. For this reason, preclinical studies are needed to better understand tumor biology with the aim to develop new targeted therapeutics. Currently, these studies are mainly based on in vitro testing, since cell lines, and in particular patient-derived models, represent a reliable and easy to handle tool for investigation. In the present review, we summarize the most important models currently available in the field, focusing in particular on the three-dimensional spheroid/organoid model. This innovative approach for studying tumor biology better represents tissue architecture and cell–cell as well as cell–microenvironment crosstalk, which are fundamental steps for tumor cell proliferation and survival.

Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH) for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (micro)environment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D) cell cultures and patient-derived tumor xenografts (PDX) as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue.

Objective: The development of new targeted therapeutics has allowed an essential improvement in carcinoma treatment. For sarcomas, however, the main approach is still the combination of surgery, chemotherapy and radiation, which is due to their high heterogeneity, with more than 70 histopathological subtypes, and the limited knowledge of the molecular drivers of tumor development and progression. Here we show that patient-derived 3D (PD3D) cell culture models allow for an in vitro system to systematically test compounds and combos in a semi-automated way, generating a pre-clinical dataset that in combination with clinical data, genomic and proteomics profiles may help to better understand the biology and ultimately identify more potent treatment regimens. Methods: Fresh surgical specimen underwent several steps of dissociation. Cell aggregates were then seeded into 24w plates in matrix-like scaffolds and grown until >100μm. Organoids were then harvested, transferred to 384w plates and treated with a set of compounds that resemble standard-of-care treatments and novel compounds. Finally, viability was calculated. In parallel, protein extracts were used for DigiWest, a multiplexed protein profiling assay allowing to interrogate up to 800 (phospho)-proteins. Results: Of 49 cases with a biopsy, 23 had too little material available. Of these 23 samples, 5 were reported as sarcoma tissue afterwards, while 5 of the taken 26 samples were not sarcomas according to the final histopathology. Of all sarcomas, 90% (19/21) were taken from tumors localized at the extremities, the rest was located at the trunk. 52% (11/21) were growing in short term cell culture at least to passage 1 (p1), 28% (6/21) were growing for long term analyses. Two of those six were myxoid liposarcomas, two were undifferentiated pleomorphic sarcomas or classified as not otherwise specified (UPS/NOS), one was a myxoid liposarcoma and one a biphasic synovial sarcoma. Here we show that it is feasible to generate organoids from sarcoma tissues for extensive characterization in order to better understand their biology and mechanisms of treatment. High-throughput drug screening allows for an profiling of pharmacokinetic properties of individual sarcomas. Using the same material for additional (phospho)-proteomics provides multiple layers of understanding. Conclusion: At present, the structure of clinical trials is not amenable to N of 1 studies, so applying the information garnered from this platform, particularly combination therapy drug screens, remains a significant hurdle. The major limitation to the establishment of organoid cultures was insufficient amounts of fresh tissue with viable tumor cells. Increasing the tumor tissue available for organoid production would lead to a greater success rate. Nevertheless, by their recapitulation of the donor tissue architecture, they provide an interesting and important tool to study the huge variety of soft-tissue tumors. Citation Format: Manuela Gaebler, Alessandra Silvestri, Peter Reichardt, Eva Wardelmann, Guido Gambara, Johannes Haybaeck, Philipp Stroebel, Maya Niethard, Gerrit Erdmann, Christian R. Regenbrecht. Patient-derived sarcoma models: First results from the SARQMA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 469.

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