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改变的机制、功能和治疗后果。因此，CRU 5002的所有科学项目都唯一地依赖于代表各自项目感兴趣的分子亚型的分子表征PDAC模型的可用性。因此，核心项目1 （CP1）为整个CRU进行的转化研究生成临床前PDAC模型。具体来说，我们将利用从大学医学中心Göttingen分子胰腺项目（MolPAC）注册的PDAC患者中切除的PDAC材料，用于生成和扩增患者衍生的异种移植（PDX）模型、类器官和PDX衍生的原代PDAC细胞。通过结合免疫组织化学方法、多基因面板测序和RNA-Seq分析，探讨临床前PDAC模型的亚型表征和分子改变的纵向稳定性。考虑到加入MolPAC项目的PDAC患者进行了全面的临床记录，在整个CRU的这些临床前模型中收集的所有机制、功能和治疗发现都可以与临床注释相关联，从而为PDAC亚型特异性基因组动态改变的预后和治疗预测价值提供信息。此外，CP1将建立一个用于CRU 5002及以后的类器官生物库，并将比较来自同一供体患者的pdx模型和类器官的亚型一致性。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进行的治疗研究以及未来的转化研究的结构性措施，我们将建立一个体外治疗验证平台，以评估PDAC中有效靶向基因组动态改变的亚型特异性，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.