TY  - JOUR
AU  - Umbaugh, Charles Samuel
AU  - Groth, Marie
AU  - Erkut, Cihan
AU  - Lee, Kwang
AU  - Marinho, Joana
AU  - Linder, Simon
AU  - Iser, Florian
AU  - Kapp, Jonas
AU  - Schroeter, Petra
AU  - Dolaner, Simay
AU  - Kayserili, Asli
AU  - Helm, Dominic
AU  - Schneider, Martin
AU  - Hartmann, Julia
AU  - Walch, Philipp
AU  - Barth, Thomas F E
AU  - Mellert, Kevin
AU  - Dreier, Birgit
AU  - Schaefer, Jonas V
AU  - Plückthun, Andreas
AU  - Fröhling, Stefan
AU  - Scholl, Claudia
TI  - Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma.
JO  - Science advances
VL  - 11
IS  - 36
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2025-01838
SP  - eadu2796
PY  - 2025
N1  - #EA:B290#EA:B340#LA:B290#LA:B340#
AB  - 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.
KW  - Humans
KW  - Animals
KW  - Gene Regulatory Networks
KW  - Mice
KW  - Chordoma: metabolism
KW  - Chordoma: genetics
KW  - Chordoma: drug therapy
KW  - Chordoma: pathology
KW  - Cell Line, Tumor
KW  - Gene Expression Regulation, Neoplastic: drug effects
KW  - Proteomics
KW  - Xenograft Model Antitumor Assays
LB  - PUB:(DE-HGF)16
C6  - pmid:40901948
DO  - DOI:10.1126/sciadv.adu2796
UR  - https://inrepo02.dkfz.de/record/304303
ER  -