Combination therapy offers new treatment approach for pancreatic cancer
Pancreatic cancer, also known as pancreatic ductal adenocarcinoma, is one of the most aggressive types of cancer. Despite advances in modern medicine, survival rates remain very low, and many patients develop resistance to available treatments as tumor cells rapidly adapt through alternative mechanisms. Researchers from the University Medical Center Göttingen (UMG), the Technical University of Munich (TUM), the Georg-Speyer-Haus Frankfurt, and Charité – Universitätsmedizin Berlin have now jointly identified a novel therapeutic strategy that could significantly improve treatment efficacy.
Under the leadership of Priv.-Doz. Dr. Matthias Wirth, head of the research group “Functional Genomics and Therapy Resistance,” and Prof. Dr. Günter Schneider, head of Translational Research, both at the Department of General, Visceral, and Pediatric Surgery at UMG, together with Prof. Dr. Ulrich Keller, Director of the Department of Hematology, Oncology, and Tumor Immunology at Charité – Universitätsmedizin Berlin, the research team demonstrated that simultaneous inhibition of the PI3Kα/δ and SUMO signaling pathways selectively kills pancreatic cancer cells. In animal models, this combination therapy markedly reduced tumor growth and additionally activated the immune system to attack the cancer cells.
“Our work shows that only the combined inhibition of both signaling pathways – PI3Kα/δ and SUMO – leads to successful elimination of tumor cells. This represents a highly promising strategy for urgently needed new treatment options,” says Prof. Dr. Günter Schneider, one of the senior authors of the study.
The research was supported by the Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe, Hector Stiftungen, Wilhelm Sander-Stiftung und Deutschen Konsortium für Translationale Krebsforschung (DKTK). The results were published in the journal Gastroenterology.
Original publication:
Hazal Köse, Christian Schneeweis, Philipp Putze, Constanza Tapia Contreras, Laura Ferreiro, Leonie Witte, Ilaria Deidda, Frederik Herzberg, Sophie Ebert, Juraj Jakubik, Leoni Moldaner, Jovan Todorovic, Isabelle Träger, Chuanbing Zhang, Uta M. Demel, Elisabeth Hessmann, Marieluise Kirchner, Simone Rhein, Jens Hoffmann, Zuzana Tatarova, Michael Ghadimi, Dieter Saur, Kai Kappert, Phillipp Mertins, Günter Schneider, Ulrich Keller, Matthias Wirth. Targeting mutual dependence of PI3Kα/δ and SUMO signaling in pancreatic cancer. Gastroenterology (2025), DOI: 10.1053/j.gastro.2025.08.018
New insights: Targeting two vulnerabilities at once
Pancreatic cancer is characterized by an exceptional resistance to standard therapies. Even new targeted drugs that block specific cancer-related genes often lose their effectiveness quickly, as tumor cells develop compensatory escape mechanisms. The PI3K signaling pathway plays a central role in the development and progression of pancreatic cancer. Previous attempts to therapeutically inhibit this pathway have been largely unsuccessful. Researchers in Göttingen discovered that when the PI3K pathway is blocked, cancer cells compensate by activating another cellular mechanism – SUMOylation. In this process, small proteins called SUMO proteins attach to target proteins, altering their function and stability, thereby helping cancer cells adapt to stress conditions.
“For the first time, we were able to show that these two signaling pathways are mutually dependent. When one is blocked, the cancer cells activate the other as a compensatory mechanism,” explains Prof. Dr. Ulrich Keller, senior author of the study.
“The combination therapy works on multiple levels. It not only directly kills cancer cells but also activates the immune system. Immune cells were able to infiltrate the tumor more effectively and destroy the cancer cells. This dual effect – direct tumor cell death and immune activation – makes the approach particularly promising,” adds Priv.-Doz. Dr. Matthias Wirth, senior author of the study.
A significant therapeutic approach for patients
Further studies will be needed to develop this approach into a clinical therapy. “Our findings reveal that the simultaneous inhibition of PI3K and SUMO uncovers a previously untapped vulnerability of pancreatic cancer,” says Priv.-Doz. Dr. Matthias Wirth.
Scientific expert: Priv.-Doz. Dr. Matthias Wirth, Department of General, Visceral, and Pediatric Surgery, Phone +49 551 / 39-65161, matthias.wirth(at)med.uni-goettingen.de
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