Translational platform for PDAC models and drug response validation

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The prime goal of the CRU 5002 is to study the mechanistic, functional and therapeutic consequences of subtype-specific genome dynamic alterations in pancreatic cancer (PDAC). Consequently, all scientific projects of the CRU 5002 univocally rely on the availability of molecularly characterized PDAC models representing the respective project´s molecular subtype of interest. Hence, Core Project 1 (CP1) generates preclinical PDAC models for translational studies performed throughout the CRU. Specifically, we will utilize resected PDAC material from PDAC patients enrolled in the Molecular Pancreas Program (MolPAC) of the University Medical Center Göttingen for the generation and expansion of Patient-Derived-Xenograft (PDX) models, organoids and PDX-derived primary PDAC cells. Subtype-characterization and longitudinal stability of molecular alterations in preclinical PDAC models are explored by combining immunohistochemical approaches, multigene panel sequencing and RNA-Seq analysis. Given that PDAC patients enrolled in the MolPAC program undergo thorough clinical documentation, all mechanistic, functional and therapeutic findings collected in these preclinical models throughout the CRU can be correlated with clinical annotations and thus inform on the prognostic and therapy-predictive value of subtype-specific genome dynamic alterations in PDAC. Further, CP1 will establish an organoid biobank for utilization in the CRU 5002 and beyond and will compare PDX-models and organoids derived from identical donor patients for their subtype-consistency. Moreover, CP1 provides consulting for all experimental studies performed in translational PDAC models and supervises therapeutic intervention studies performed in the framework of the CRU 5002. Finally, and as a structural measure for treatment studies performed throughout the CRU as well as for future translational studies, we will establish an in vitro therapy validation platform to evaluate the subtype-specificity of efficient targeting of genome dynamic alterations in PDAC and to elucidate the most promising drug combinations in preparation for an investigator-initiated clinical trial.