(P 265) DEVELOPMENT OF THERAPEUTIC STRATEGY FOR DESMOID TUMOR WITH NOVEL PATIENT-DERIVED PRECLINICAL MODEL

Objective: Desmoid tumor (also known as aggressive fibromatosis) is a rare tumor and a type of mesenchymal neoplasms. Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, tumor may recur adjacent to the site of surgical resection, underscoring the limitations of surgery in the palliative setting. Many clinical studies on desmoid are ongoing. However, there are few translational studies for future development and improvement. One of the reason is the absence of preclinical models for evaluation. An effective therapeutic resource for the desmoid tumor is needed to maintain quality of life and prolong survival.

Methods: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. And then we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9,235). Transcriptomic data was normalized throughout the three cohorts to reduce batch effect.
Secondly, while conducting NGS, we established the novel patient-derived preclinical models (n=2) for the validation of treatment strategy. It had the same gene alteration of primary tissue. In our preclinical model, we evaluated pharmacological inhibition antidrug that were selected by the results of genomic and transcriptomic analysis of desmoid.

Results: As the results of genomic and transcriptomic analyses, we discovered specific gene sets. And it was related to the TGF-β signaling pathway. Based on the evidence (the NGS analyses, pathological features; strong positive expression of CTNNB1, and alpha-SMA, and the interaction of beta-catenin and TGF-β), we selected the combination treatment TGF-β inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-β inhibitor was more effective for tumor suppression than monotherapy.

Conclusion: We found the clinical & bioinformatical preclinical foundation that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Based on this evidence, as an effective drug, vactosertib was used in evaluation together with imatinib (combination treatment). In our preclinical models, we evidenced the usefulness of TGF-β inhibitor. Also, we could find some examples in clinical trials.