Patient‐specific logic models of signaling pathways from screenings on cancer biopsies to prioritize personalized combination therapies

Molecular Systems Biology

Jessica Wappler¹  Thorsten Cramer¹  Federica Eduati²  Christoph A Merten²  Julio Saez‐Rodriguez³  Patricia Jaaks⁴  Mathew J Garnett⁴ 

[1] Department Surgery Molecular Tumor Biology RWTH University Hospital Aachen Germany;European Molecular Biology Laboratory (EMBL) Genome Biology Unit Heidelberg Germany;European Molecular Biology Laboratory European Bioinformatics Institute (EMBL‐EBI) Hinxton UK;Wellcome Trust Sanger Institute Hinxton UK;

关键词: drug combinations;    logic modeling;    patient‐specific models;    precision oncology;    signaling pathways;   

DOI  :  10.15252/msb.20188664

来源: DOAJ

【 摘 要 】

Abstract Mechanistic modeling of signaling pathways mediating patient‐specific response to therapy can help to unveil resistance mechanisms and improve therapeutic strategies. Yet, creating such models for patients, in particular for solid malignancies, is challenging. A major hurdle to build these models is the limited material available that precludes the generation of large‐scale perturbation data. Here, we present an approach that couples ex vivo high‐throughput screenings of cancer biopsies using microfluidics with logic‐based modeling to generate patient‐specific dynamic models of extrinsic and intrinsic apoptosis signaling pathways. We used the resulting models to investigate heterogeneity in pancreatic cancer patients, showing dissimilarities especially in the PI3K‐Akt pathway. Variation in model parameters reflected well the different tumor stages. Finally, we used our dynamic models to efficaciously predict new personalized combinatorial treatments. Our results suggest that our combination of microfluidic experiments and mathematical model can be a novel tool toward cancer precision medicine.

【 授权许可】

Unknown