AACR 2026 Poster 4616

Integrated Organoid Screening Approaches Enable Preclinical Assessment of Protein Degrader Efficacy and Target Engagement

Marten Hornsveld, Dennis van der Grinten, Dorith Verstegen, Shannon Kouters, Esther Kingma, Tomas Veenendaal, Mariusz Madej, Aaron Hua, Jinxin Wang, Lenno Krenning, Jessie Wang, Marrit Putker, Ludovic Bourre

Discover how integrated organoid screening enables robust evaluation of protein degrader efficacy and target engagement.

Molecular glues and protein degraders represent a promising therapeutic class, yet assessing efficacy and target engagement in complex systems remains challenging. This study demonstrates how patient-derived organoids combined with high-content imaging and CRISPR-based tools enable scalable, physiologically relevant screening. By linking degradation, viability, and target engagement, this platform supports more predictive preclinical decision-making.

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• Evaluate degrader efficacy across diverse models: Screen protein degraders across a panel of patient-derived organoids to capture response variability.
  
  
• Quantify target engagement and degradation
  
  
• Identify resistance mechanisms: Apply CRISPR/Cas9-edited organoids to investigate drivers of degrader resistance.
  
  
• Correlate in vitro and in vivo response: Demonstrate alignment between organoid screening results and PDX model outcomes.
  
  
• Enable scalable, predictive screening: Combine organoid platforms with automated imaging for high-throughput, translational workflows.

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