Therapeutic Implications of TGF-β Pathway in Desmoid Tumor Based on Comprehensive Molecular Profiling and Clinicopathological Properties

SIMPLE SUMMARY: Desmoid tumors are rare and aggressive tumors that currently do not receive satisfactory systemic treatment. Thus, an in-depth study into desmoid tumors was needed. In this study, we performed the comprehensive molecular profiling for desmoid tumor samples from patients and found the druggable biomarker. Notably, the TGF-β signaling pathway was consistently identified as enriched in desmoid tumors using comprehensive molecular profiling. It suggested that therapeutic interventions targeting TGF-β in fibroblasts using TGF-β receptor inhibitors may be clinically beneficial in patients with desmoid tumors. After that, we validated it by using a desmoid patient-derived primary cell model that displayed high concordance with desmoid primary tissues. Finally, we proved that that the inhibition of the TGF-β pathway is useful as a potential treatment for patients with desmoid tumors. ABSTRACT: (1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. 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 = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-β signaling pathway. Moreover, we selected the combination treatment comprising 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. (4) Conclusion: We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.