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Patient-derived cell lines and xenografts from sarcoma patients as models for therapeutic decision making


Academic year: 2022

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Suzanne Fischer


Suzanne Fischer (1,2,3), David Creytens (2,4), Gwen Sys (2,5), Lore Lapeire (2,6), An Hendrix (1,2) and Olivier De Wever (1,2).

(1) Laboratory of Experimental Cancer Research, Ghent University, Ghent, Belgium (2) Cancer Research Institute Ghent (CRIG), Ghent, Belgium

(3) Department of Gastro-Intestinal Surgery, Ghent University Hospital, Ghent, Belgium (4) Department of Pathology, Ghent University Hospital, Ghent, Belgium

(5) Department of Orthopedic Surgery and Traumatology, Ghent University Hospital, Ghent, Belgium (6) Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium

Introduction. Sarcomas are a diverse group of rare, malignant tumors. Once metastasized, sarcoma patients have a 5-year overall survival of 16%. Survival rates have stagnated over the last 20 years.

The main reason is the rarity of the disease with more than 80 subtypes, which prohibits design of large, randomized trials and subtype-specific clinical studies. There is a great need for preclinical models in sarcoma research that recapitulate the heterogeneity of the tumor, and simulate the clinical course of the patient.

Goal. Establishment of patient-derived cell lines (PDC) for high-throughput drug testing (HTT) in 2D and 3D conditions. Establishment of orthotopic patient-derived xenografts (PDX), clinically relevant for the systemic spread of sarcoma.

Methods. Tumor samples were collected at the Ghent University Hospital during tumor resection, and minced into 1-2mm3 pieces. PDCsamples were dissolved in a DNase I/Collagenase II solution, using a GentleMax©protocol and maintained under standard cell culture conditions. PDXsamples were implanted orthotopically on the lower limb in a NSG mouse and followed with MRI. Once the tumor reached a size of > 250 mm3, the limb was amputated. Once metastasis occurred, the animals were euthanized. Tumor histology was evaluated by a pathologist.

Results. Five PDCs have been established, and HTT identified active compounds were shared by some of the cell cultures examined, others were cell type-specific, underscoring how the heterogeneity of cancer can influence the cellular responses to drug treatment. Six PDXs have been developed, 4 using primary tumor and 2 using lung metastasis. Metachronous metastasis occurred in 3 out of 4 PDX using primary tumor; and 2 out of 2 PDX using lung metastasis. Second generations have been set-up for both primary and metastasis PDX tissue.

Conclusion. PDC and orthotopic PDX recapitulate the heterogeneity of the tumor, and simulate the clinical course of the patient. A PDX clinical trial will be designed to assess the potential of HTT- identified treatment modalities. Our results provide critical insights to guide development of high- throughput and validation platforms in a clinically relevant setting.


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