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

剖析 Pdk1 信号在胰腺癌中的作用以开发新的治疗策略

• 批准号: 360394750
• 负责人: Professor Dr. Dieter Saur, since 7/2019
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin II: Gastroenterologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/360394750?language=en
• 关键词: Dissecting; role; Pdk1; signalling; pancreatic

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.

胰腺导管腺癌（PDAC）是一种高度侵袭性的疾病。它具有极强的治疗抵抗力，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，在忠实再现人类疾病的基于 Cre/loxP 的基因工程小鼠模型中，PI3K-Pdk1 信号通路对于 KrasG12D 驱动的胰腺癌形成至关重要。最近已经清楚，肿瘤进展和维持的信号传导要求可能与将表型正常细胞转化为癌细胞所需的途径不同。由于对于人类癌症的治疗，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。由于基于 Cre/loxP 的经典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角度验证已建立肿瘤中的治疗靶点。这是 Cre/loxP 系统的一个重要瓶颈，也是临床前研究的速率限制。我们通过结合 Flp/frt 和 Cre/loxP 开发了一种新型诱导型双重组酶系统 (DRS)，以改善胰腺癌的基因工程小鼠模型。我们的模型能够对体内原发肿瘤的治疗靶点进行遗传验证。在拟议的研究项目中，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 进展、维持和转移中的作用。我们将使用基于 DRS 的新型模型依次使 PI3K-Pdk1 信号转导的关键效应器基因失活并研究相关漏洞。这种方法将带来对 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的重要见解，并将为这种令人沮丧的疾病的新治疗策略开辟新的视野。