No. 51

Rare bone tumors: Tailor-made mini-proteins switch off tumor drivers

Das Bild zeigt ein 3D-Modell eines Proteins mit mehreren spiralförmigen Strukturen in Orange und lila. Kleinere Moleküle sind in einer Kombination von Farben am unteren Teil des Modells dargestellt, was chemische Bindungen andeutet.
Structural model of a DARPin

Chordomas are rare bone tumors for which there are currently no effective drugs. A research team from the German Cancer Research Center (DKFZ) and the National Center for Tumor Diseases (NCT) Heidelberg has now developed a promising approach: Tailor-made mini-proteins specifically block the central driver of tumor development. In the result, they slowed the growth of chordoma cells in the laboratory and in a mouse model, while also revealing further molecular vulnerabilities of the tumor that could be addressed with already approved drugs.

Chordomas are rare bone tumors that usually develop at the base of the skull or on the spine. They grow aggressively locally, often recur, and respond poorly to chemotherapy. The standard treatment is surgery and radiation, and there is a lack of effective drugs.

The transcription factor TBXT, which plays a central role in embryonic development, is considered the key driver of chordoma cancer. TBXT is not normally found in adults, but is overexpressed in over 90 percent of chordomas.Transcription factors such as TBXT, which act within the cell nucleus, are considered very difficult to target with normal drugs. However, the team led by Claudia Scholl (DKFZ) and Stefan Fröhling (NCT Heidelberg and DKFZ) has found a solution: they inhibited TBXT with tailor-made small binding proteins called DARPins.

The acronym stands for “Designed Ankyrin Repeat Proteins”. DARPins act similarly to antibodies, but can be easily produced in bacteria, for example, and, unlike antibodies, can also bind to target molecules within cells.

Using a technique that enables high-throughput screening of protein interactions, the researchers, in collaboration with Andreas Plückthun from the University of Zurich, succeeded in identifying DARPins that specifically dock to the DNA-binding domain of TBXT, thereby preventing the transcription factor from binding to DNA.

In chordoma cell cultures, it was confirmed that the selected DARPins selectively blocked the binding of TBXT to its target DNA. This slowed cell division, inhibited tumor growth in mice, and triggered signs of senescence and differentiation of the tumor cells.

Until now, DARPins have been developed against cell surface or cytoplasmic proteins, and some of these agents are already being tested in clinical trials. “We have now demonstrated for the first time that DARPins can also be effective against target proteins in the cell nucleus – this is a proof of concept with implications beyond chordoma,” says study leader Claudia Scholl.

What exactly happens in chordoma cells when the TBXT effect is blocked by DARPins? This is important to know because, in addition to TBXT itself, the genes activated by the transcription factor could also represent therapeutic targets that could be addressed alone or in combination with future TBXT-targeted drugs.

By systematically mapping all TBXT-dependent genes, the Heidelberg team identified entire networks of genes that are controlled by TBXT and whose disruption acts as a growth inhibitor for cancer cells. This also revealed signaling pathways that can be targeted with already approved drugs. For example, the dependence of chordoma cells on the activity of the JAK-STAT signaling pathway, which is co-driven by TBXT, turned out to be a therapeutic Achilles' heel. This makes the cancer cells sensitive to drugs that block the enzyme JAK2which is a central hub of this signaling pathway.

“The dependence on JAK-STAT signaling shows us a new therapeutic strategy that we can test relatively quickly, as several established JAK2 inhibitors are already available – drugs that are already approved for other diseases,” explains first author Sam Umbaugh. Co-study leader Stefan Fröhling, director at NCT Heidelberg, adds: “Our results open up two perspectives: On the one hand, TBXT-blocking DARPins provide tools for further research on this difficult tumor. On the other hand, they reveal concrete starting points for therapies that could be investigated in future clinical trials.”

Publication:
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 WalchThomas F.E. Barth, Kevin Mellert, Birgit Dreier, Jonas V. Schaefer, Andreas Plückthun, Stefan Fröhling, and Claudia Scholl:
Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma. Science Advances 2025, DOI: https://www.science.org/doi/10.1126/sciadv.adu2796

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About DKFZ

With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.

To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:

  • National Center for Tumor Diseases (NCT, 6 sites)
  • German Cancer Consortium (DKTK, 8 sites)
  • Hopp Children's Cancer Center (KiTZ) Heidelberg
  • Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
  • DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
  • National Cancer Prevention Center (jointly with German Cancer Aid)

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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