Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

作者：Charles S. Umbaugh, Marie Groth, Cihan Erkut, Kwang Seok Lee, Joana Marinho, Simon Linder, Florian Iser, Jonas N. Kapp, Petra Schroeter, Simay Dolaner, Asli Kayserili, Dominic Helm, Martin Schneider, Julia Hartmann, Philipp Walch, Thomas F.E. Barth, Kevin Mellert, Birgit Dreier, Jonas V. Schaefer, Andreas Plückthun, Stefan Fröhling, Claudia Scholl · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adu2796 · 被引用次数：6 · 研究领域：Bone Tumor Diagnosis and Treatments、Sarcoma Diagnosis and Treatment、interferon and immune responses

The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT's regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.