Translational platform for PDAC models and drug response validation

CRU 5002的主要目标是研究胰腺癌(PDAC)亚型特异性基因组动态变化的机制、功能和治疗后果。因此，CRU5002的所有科学项目都明确地依赖于代表各自项目的S感兴趣分子亚型的分子表征的PDAC模型的可用性。因此，核心项目1(CP1)为整个CRU中执行的转译研究生成临床前PDAC模型。具体地说，我们将使用从参加大学医学中心Göttingen分子胰腺计划(MolPAC)的PDAC患者切除的PDAC材料来生成和扩增患者来源的异种移植(PDX)模型、器官和PDX来源的原代PDAC细胞。结合免疫组织化学方法、多基因面板测序和RNA-Seq分析，探讨了临床前PDAC模型中分子改变的亚型特征和纵向稳定性。考虑到参加MolPAC计划的PDAC患者都经过了全面的临床记录，在CRU的这些临床前模型中收集的所有机制、功能和治疗结果都可以与临床注释相关联，从而了解PDAC亚型特定基因组动态变化的预后和治疗预测价值。此外，CP1将建立一个用于CRU 5002及以上的有机生物库，并将比较来自相同供体患者的PDX模型和有机类化合物的亚型一致性。此外，CP1还为在翻译PDAC模型中进行的所有实验研究提供咨询，并监督在CRU 5002框架下进行的治疗干预研究。最后，作为整个CRU中进行的治疗研究以及未来翻译研究的结构性措施，我们将建立一个体外治疗验证平台，以评估有效靶向PDAC基因组动态变化的亚型特异性，并阐明最有希望的药物组合，为研究人员发起的临床试验做准备。

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.