Researchers at the German Cancer Research Center (DKFZ) and the National Center for Tumor Diseases (NCT) Heidelberg have elucidated the molecular genetic background of a newly discovered sarcoma subtype that occurs in children and adults. The findings have led to several potential therapeutic approaches that could be tested clinically in the future.
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD).
Soft-tissue sarcomas are malignant tumors of the connective tissue. They are rare and characterized by histologic diversity and a variable clinical course, ranging from slow-growing to very aggressive and metastatic. Soft-tissue sarcomas also include the group of rhabdomyosarcomas, which originate from skeletal muscle cells. Researchers at DKFZ and NCT Heidelberg have investigated a recently discovered rhabdomyosarcoma subtype characterized by fusions of the TFCP2 gene with various partner genes.
Rhabdomyosarcomas with TFCP2 fusions occur primarily in the head and neck region and are very aggressive and usually fatal as they do not respond to standard therapies. Until now, their molecular origin was largely unknown. Claudia Scholl, Head of the Division of Applied Functional Genomics at DKFZ and NCT Heidelberg, explains: “Through our very detailed functional and mechanistic studies in the laboratory, we were able to elucidate the development of this disease and thus find weak points in the tumor cells that might be exploited therapeutically.”
The motivation to study TFCP2 sarcomas in the laboratory resulted from the DKFZ/NCT/DKTK MASTER precision oncology program, in which these tumors, which were still unknown at the time, had been observed several times. In addition, the researchers integrated patients from the INFORM program, which – in a similar approach to MASTER – focuses on children with advanced and difficult-to-treat cancers. This resulted in a joint, highly collaborative endeavor across scientific and clinical disciplines.
Through the molecular analysis of patient tumors and detailed laboratory tests, the researchers were able to show that tumors with TFCP2 fusions likely represent a separate sarcoma subtype that should not be classified as rhabdomyosarcoma. In addition, several potential approaches were identified for the targeted treatment of this aggressive disease.
Stefan Fröhling, Managing Director at NCT Heidelberg and Head of the Division of Translational Medical Oncology at DKFZ, emphasizes: “The study provides important results and is a prime example of the entire translational cancer research cycle. Clinically anchored analyses in MASTER and INFORM have led to in-depth investigations in the laboratory. The new therapeutic targets discovered there will be fed back into the clinic and hopefully improve the treatment of a patient group whose disease has been underresearched and remains an unmet medical need.”
MASTER: Molecularly Aided Stratification for Tumor Eradication Research
INFORM: INdividualized Therapy FOr Relapsed Malignancies in Childhood
Publication: Julia Schöpf, Sebastian Uhrig, Christoph E. Heilig, Kwang-Seok Lee, Tatjana Walther, Alexander Carazzato, Anna Maria Dobberkau, Dieter Weichenhan, Christoph Plass, Mark Hartmann, Gaurav D. Diwan, Zunamys Carrero, Claudia R. Ball, Tobias Hohl, Thomas Kindler, Patricia Rudolph-Hähnel, Dominic Helm, Martin Schneider, Anna Nilsson, Ingrid Øra, Roland Imle, Ana Banito, Robert B. Russell, Barbara C. Jones, Daniel B. Lipka, Hanno Glimm, Daniel Hübschmann, Wolfgang Hartmann, Stefan Fröhling, Claudia Scholl: Multi-Omic and Functional Analysis for Classification and Therapeutic Targeting of Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions; Nature Communications, doi: 10.1038/s41467-023-44360-2