KFO 216: Characterisation of the Oncogenic Signalling Network in Multiple Myeloma: Development of Targeted Therapies

临床研究单位的基本假设是，在多发性骨髓瘤中，恶性表型是由多个信号通路而不是单个信号通路的放松引起的，这些信号通路共同构成了致癌信号网络。因此，我们假设这个网络中的差异可能允许对这种疾病的新亚群进行功能定义。因此，这个临床研究单位的目标是尝试对致癌信号网络进行广泛的功能表征，以允许开发新的和有效的治疗方案。这一目标将通过两种相辅相成的方法来实现：(1)结合原代骨髓瘤细胞的功能、分子和遗传体外特征，(2)发展不同的遗传小鼠模型，以研究和验证体内原代人骨髓瘤样本的致癌途径。这些动物模型最终将用于新的治疗方法的临床前研究。我们以前的工作导致了一些在骨髓瘤细胞中被激活的信号系统的鉴定，例如RAS-、NF-kB-和应激反应通路(例如热休克蛋白通路)。我们的目的是尽可能准确地评估这些通路在骨髓瘤中的功能重要性，并分析它们是否以及在多大程度上相互合作。在一种补充方法中，我们计划通过使用基于shRNA的筛选技术来筛选仍然未知的信号通路。最后，我们将试图确定可能导致这些途径激活的遗传损伤。为此，我们将应用新的基因技术，例如高通量测序。这些结果应该有助于更好地了解这种疾病的功能和分子异质性。它们还应促进确定新的治疗相关靶点，并实施可专门针对适当的骨髓瘤亚群设计的新的治疗方法。在这个临床研究单位的框架内，来自维尔茨堡大学六个不同研究所的20名科学家在六个子项目和三个核心设施(z项目)中进行合作。与乌尔姆大学内科二系的医生和科学家也进行了密切的合作。

The underlying hypothesis for the Clinical Research Unit is the assumption that in multiple myeloma the malignant phenotype results from deregulation not of a single but of a number of signalling pathways, and that these collectively constitute an oncogenic signalling network. Consequently, we assume that differences in this network may permit functional definition of novel subgroups of this disease. It is therefore the aim of this Clinical Research Unit to attempt an extensive functional characterisation of the oncogenic signalling network to permit the development of novel and effective therapeutic options. This aim will be pursued via two complementing methodical approaches: (1) a combination of functional, molecular and genetic ex vivo characterisations of primary myeloma cells, and (2) the development of different genetic mouse models to study and to verify the oncogenic pathways in primary human myeloma samples in vivo. These animal models will eventually serve in preclinical studies of novel therapeutic approaches. Our previous work has led to the identification of a number of signalling systems that are activated in myeloma cells, such as Ras-, NF-kB- and stress-response-pathways (e.g. the heat shock protein pathway). Our aim is to appraise the functional importance of these pathways in myeloma as accurately as possible and to analyse if and to what extent they cooperate with each other. In a complementary approach we plan to screen for still unknown signalling pathways by using shRNA-based screening techniques. Finally, we will try to identify the genetic lesions that might lead to the activation of these pathways. To this end, we will apply novel genetic technologies such as for example high-throughput sequencing. The results should help to obtain a better understanding of the functional and molecular heterogeneity of this disease. They should also promote identification of novel therapeutically relevant targets and implementation of novel treatment approaches that may be designed to specifically target suitable myeloma subgroups. Within the framework of this Clinical Research Unit, 20 scientists from six different institutes of Wuerzburg University cooperate in six subprojects and three core facilities (z-projects). There is also a close cooperation with physicians and scientists from the department of internal medicine II at the Ulm University.