Dissecting the role of Pdk1 signalling in pancreatic cancer to develop novel therapeutic strategies

胰腺导管腺癌（PDAC）是一种高度侵袭性的疾病。它具有极强的治疗耐药性，几乎总是致命的。因此，迫切需要新的治疗策略。我们已经证明，PI3K-Pdk1信号通路对于krasg12d驱动的胰腺癌形成至关重要，在一个基于Cre/ loxp的基因工程小鼠模型中，该模型忠实地再现了人类疾病。最近，肿瘤进展和维持的信号要求与将表型正常细胞转化为癌细胞所需的途径不同，这一点已经变得很清楚。由于在人类癌症治疗中，肿瘤进展和维持比肿瘤起始更重要，因此特定基因或途径与肿瘤进展/维持的相关性至关重要。由于经典的基于Cre/loxP的小鼠模型依赖于单个Cre重组步骤来激活胰腺中突变的Kras表达，因此几乎不可能从遗传学上验证已建立肿瘤的治疗靶点。这是Cre/loxP系统的一个重要瓶颈，也限制了临床前研究的速度。我们通过结合Flp/frt和Cre/loxP开发了一种新的诱导型双重组酶系统（DRS）来改善基因工程小鼠胰腺癌模型。我们的模型能够在体内对自体肿瘤的治疗靶点进行遗传验证。在我们提出的研究项目中，我们旨在研究PI3K-Pdk1调节的信号通路的肿瘤细胞自主功能在PDAC的进展、维持和转移中的作用。我们将使用新的基于DRS的模型依次灭活PI3K-Pdk1信号的关键效应物，并研究相关的漏洞。该方法将对PI3K-Pdk1信号在胰腺癌生物学、病理生理学和治疗耐药性中的作用产生重要见解，并将为这种令人沮丧的疾病的新治疗策略打开视野。

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease. It is extremely treatment resistant and almost invariably fatal. Therefore, novel therapeutic strategies are urgently needed. We have shown that the PI3K-Pdk1 signalling pathway is essential for KrasG12D-driven pancreatic cancer formation in a genetically engineered, Cre/loxP-based mouse model that faithfully recapitulates the human disease. Recently it has become clear that the signalling requirements for tumor progression and maintenance can be distinct from the pathways needed to transform a phenotypically normal cell into a cancer cell. Since tumor progression and maintenance is more important than tumor initiation for the treatment of human cancer, the relevance of a particular gene or pathway for tumor progression/maintenance is of paramount importance. Because the classical Cre/loxP based mouse models rely on a single Cre recombination step to activate mutant Kras expression in the pancreas, it is almost impossible to validate therapeutic targets in established tumors genetically. This is a significant bottleneck of the Cre/loxP system and rate limiting for pre-clinical research. We have developed a novel inducible dual-recombinase system (DRS) by combining Flp/frt and Cre/loxP to improve genetically engineered mouse models of pancreatic cancer. Our model enables the genetic validation of therapeutic targets in autochthonous tumors in vivo. In the proposed research project we aim at investigating the role of tumor-cell autonomous functions of the PI3K-Pdk1 regulated signalling pathway for progression, maintenance and metastasis of PDAC. We will use the novel DRS based model to sequentially inactivate critical effectors of PI3K-Pdk1 signalling genetically and investigate associated vulnerabilities. This approach will lead to important insights into the role of PI3K-Pdk1 signalling in pancreatic cancer biology, pathophysiology and therapeutic resistance and will open the horizon for novel treatment strategies for this dismal disease.