Deciphering MYC-assoziated Vulnerabilities to develop pancreatic cancer subgroup-specific therapies

• Applicant: Professor Dr. Günter Schneider
• Subject Area: Gastroenterology
• Term: from 2016 to 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317782399

• Final Report Year: 2025

Final Report Abstract

Pancreatic cancer, particularly an aggressive form driven by a protein called MYC, is notoriously difficult to treat. Our research uncovered new ways to attack these MYC-driven tumors by focusing on two key approaches. First, we found that drugs blocking a protein called PRMT5 are especially effective against pancreatic cancers with high MYC levels. These PRMT5 inhibitors caused cancer cells to self-destruct, stop multiplying, and lose their energy supply. However, some tumors developed resistance by activating alternative survival mechanisms, leading us to successfully combine PRMT5 inhibitors with other drugs that target these backup pathways for stronger anti-cancer effects. We also investigated how pancreatic cancer cells escape different treatments. While long treatment with standard chemotherapy (FOLFIRINOX) caused surviving cancer cells to switch off MYC and turn on a stress-defense protein called NRF2, inhibition of the mTOR kinase actually made cancer cells more dependent on MYC. This discovery led us to combine mTOR inhibitors with drugs that indirectly block MYC, which powerfully suppressed tumor growth in our laboratory models. These findings are important because they suggest we can develop more effective, personalized treatment strategies for pancreatic cancer patients. By matching specific drugs (like PRMT5 inhibitors) to a tumor's molecular features (like high MYC levels) and using smart drug combinations to prevent resistance, we may significantly improve outcomes.

Publications

• Rationale for MYC imaging and targeting in pancreatic cancer. EJNMMI Research, 11(1).
  Schneider, Günter; Wirth, Matthias; Keller, Ulrich & Saur, Dieter
  
• AP1/Fra1 confers resistance to MAPK cascade inhibition in pancreatic cancer. Cellular and Molecular Life Sciences, 80(1).
  Schneeweis, Christian; Diersch, Sandra; Hassan, Zonera; Krauß, Lukas; Schneider, Carolin; Lucarelli, Daniele; Falcomatà, Chiara; Steiger, Katja; Öllinger, Rupert; Krämer, Oliver H.; Arlt, Alexander; Grade, Marian; Schmidt-Supprian, Marc; Hessmann, Elisabeth; Wirth, Matthias; Rad, Roland; Reichert, Maximilian; Saur, Dieter & Schneider, Günter
  
• Epigenetic drug screening defines a PRMT5 inhibitor–sensitive pancreatic cancer subtype. JCI Insight, 7(10).
  Orben, Felix; Lankes, Katharina; Schneeweis, Christian; Hassan, Zonera; Jakubowsky, Hannah; Krauß, Lukas; Boniolo, Fabio; Schneider, Carolin; Schäfer, Arlett; Murr, Janine; Schlag, Christoph; Kong, Bo; Öllinger, Rupert; Wang, Chengdong; Beyer, Georg; Mahajan, Ujjwal M.; Xue, Yonggan; Mayerle, Julia; Schmid, Roland M. ... & Schneider, Günter
  
• Indirect targeting of MYC sensitizes pancreatic cancer cells to mechanistic target of rapamycin (mTOR) inhibition. Cancer Communications, 42(4), 360-364.
  Schneeweis, Christian; Hassan, Zonera; Ascherl, Katja; Wirth, Matthias; Koutsouli, Stella; Orben, Felix; Krauß, Lukas; Schneider, Carolin; Öllinger, Rupert; Krämer, Oliver H.; Rad, Roland; Reichert, Maximilian; Robles, Maria S.; Saur, Dieter & Schneider, Günter
  
• A Novel AMPK Inhibitor Sensitizes Pancreatic Cancer Cells to Ferroptosis Induction. Advanced Science, 11(31).
  Schneider, Carolin; Hilbert, Jorina; Genevaux, Franziska; Höfer, Stefanie; Krauß, Lukas; Schicktanz, Felix; Contreras, Constanza Tapia; Jansari, Shaishavi; Papargyriou, Aristeidis; Richter, Thorsten; Alfayomy, Abdallah M.; Falcomatà, Chiara; Schneeweis, Christian; Orben, Felix; Öllinger, Ruppert; Wegwitz, Florian; Boshnakovska, Angela; Rehling, Peter; Müller, Denise ... & Schneider, Günter