Mini tumor models from patient-derived tissue, known as organoids, without and with therapy. Bottom: Tumors (blue) with macrophages (yellow)—immune cells that identify and destroy malignant cells. Credit: Gastroenterology (2025). DOI: 10.1053/j.gastro.2025.08.018

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.

The research team demonstrated that simultaneous inhibition of the PI3Kα/δ and SUMO signaling pathways selectively kills pancreatic cancer cells. The team was led by 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.

In animal models, this combination therapy markedly reduced tumor growth and additionally activated the immune system to attack the cancer cells. These results were published in the journal Gastroenterology.

“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. Schneider, one of the senior authors of the study.

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. 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. 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. Wirth.

More information: Hazal Köse et al, Targeting Mutual Dependence of Phosphatidylinositol-3-Kinase α/δ and Small Ubiquitin-Like Modifier Signaling in Pancreatic Cancer, Gastroenterology (2025). DOI: 10.1053/j.gastro.2025.08.018

Citation: Combination therapy for pancreatic cancer offers new treatment approach (2025, November 6) retrieved 6 November 2025 from https://medicalxpress.com/news/2025-11-combination-therapy-pancreatic-cancer-treatment.html

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