Exploiting the tumor proteome activity status for future cancer therapies
Kinases are key regulators of protein activity and phosphorylate thousands of proteins in cells. The phosphoproteome can hence be viewed as a proxy for the proteome activity status of a cell. Dysregulation of the phosphoproteome can cause diseases such as cancer. As a result, kinase inhibitors have become important drugs in oncology and nearly 50 are approved for use in humans. As they typically have a range of targets, there is enormous potential for repurposing these drugs for other cancer entities. To implement this in the clinic, it is important to better understand: i) how the phosphoproteome of an individual tumor can be functionally interpreted, ii) how and to what extent kinase inhibitors modulate the phosphoproteome and iii) which drug is the best fit for modulating the proteome activity status of a particular tumor. This information is only partially or not available from classical cancer diagnostics or genomics. Therefore, the central aim of this project is to show that ground breaking new information for the diagnosis and treatment of cancer patients will come from measuring their tumor proteome activity status (TOPAS) by quantitative mass spectrometry. To this end, the first objective is to show that modulating the TOPAS of cancer model systems by kinase inhibitors functionalizes the phosphoproteome and reveals the cellular mechanisms of action of these important medicines. The second objective is to develop and validate diagnostic drug-, protein- and pathway-centric TOPAS scores able to make treatment suggestions based on the phosphoproteomes of cancer models and tumor tissues. The third objective is to demonstrate, on the example of sarcoma patients, that TOPAS scoring adds value to decision making by molecular tumor boards. Combining the strengths of proteomics and genomics, I aim for building a comprehensive multi-omics view on tumors and will create a ‘virtual tumor board’ in ProteomicsDB to make TOPAS available to the scientific community.