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000304303 245__ $$aSelective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma.
000304303 260__ $$aWashington, DC [u.a.]$$bAssoc.$$c2025
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000304303 520__ $$aThe embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT's regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as susceptibility to pharmacologic inhibition and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.
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000304303 650_2 $$2MeSH$$aHumans
000304303 650_2 $$2MeSH$$aAnimals
000304303 650_2 $$2MeSH$$aGene Regulatory Networks
000304303 650_2 $$2MeSH$$aMice
000304303 650_2 $$2MeSH$$aChordoma: metabolism
000304303 650_2 $$2MeSH$$aChordoma: genetics
000304303 650_2 $$2MeSH$$aChordoma: drug therapy
000304303 650_2 $$2MeSH$$aChordoma: pathology
000304303 650_2 $$2MeSH$$aCell Line, Tumor
000304303 650_2 $$2MeSH$$aGene Expression Regulation, Neoplastic: drug effects
000304303 650_2 $$2MeSH$$aProteomics
000304303 650_2 $$2MeSH$$aXenograft Model Antitumor Assays
000304303 7001_ $$0P:(DE-He78)15d736cdf8dab5782e1886ec4de9b66b$$aGroth, Marie$$b1$$eFirst author
000304303 7001_ $$0P:(DE-He78)d7313b8a98b50ec1018453ef11351acc$$aErkut, Cihan$$b2$$udkfz
000304303 7001_ $$0P:(DE-He78)1121dc6777ecb3a3e48075bbd16246f2$$aLee, Kwang$$b3$$udkfz
000304303 7001_ $$00000-0001-9001-9378$$aMarinho, Joana$$b4
000304303 7001_ $$0P:(DE-He78)4e47fdea8ed35a69da75bc9a30971c49$$aLinder, Simon$$b5$$udkfz
000304303 7001_ $$0P:(DE-He78)3a5c3ccb1136028578b6bc8fe12b3019$$aIser, Florian$$b6$$udkfz
000304303 7001_ $$0P:(DE-He78)d67102d44b98abd3243bcf44928048c4$$aKapp, Jonas$$b7
000304303 7001_ $$0P:(DE-He78)93543b4d8961fb093bcf0c86db648b2b$$aSchroeter, Petra$$b8$$udkfz
000304303 7001_ $$0P:(DE-He78)9128c030ab4aecc83482354694bae75f$$aDolaner, Simay$$b9$$udkfz
000304303 7001_ $$00009-0002-0737-0664$$aKayserili, Asli$$b10
000304303 7001_ $$0P:(DE-He78)daaed5a5b968028e6e95d273150d5ab1$$aHelm, Dominic$$b11$$udkfz
000304303 7001_ $$0P:(DE-He78)0d37cc734b95fed555f2244d6fee6320$$aSchneider, Martin$$b12$$udkfz
000304303 7001_ $$0P:(DE-He78)17112a5a72f44d4df00e64edc925d674$$aHartmann, Julia$$b13
000304303 7001_ $$0P:(DE-He78)be5d291ecdf9748a9b74f3f4d37d1c5b$$aWalch, Philipp$$b14
000304303 7001_ $$aBarth, Thomas F E$$b15
000304303 7001_ $$00000-0001-6338-1857$$aMellert, Kevin$$b16
000304303 7001_ $$aDreier, Birgit$$b17
000304303 7001_ $$00000-0002-8332-4371$$aSchaefer, Jonas V$$b18
000304303 7001_ $$00000-0003-4191-5306$$aPlückthun, Andreas$$b19
000304303 7001_ $$0P:(DE-He78)f0144d171d26dbedb67c9db1df35629d$$aFröhling, Stefan$$b20$$eLast author
000304303 7001_ $$0P:(DE-He78)2c1a21d1cf5fdc9e297512c9d1354250$$aScholl, Claudia$$b21$$eLast author$$udkfz
000304303 773__ $$0PERI:(DE-600)2810933-8$$a10.1126/sciadv.adu2796$$gVol. 11, no. 36, p. eadu2796$$n36$$peadu2796$$tScience advances$$v11$$x2375-2548$$y2025
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