Opis projektu
Fosforylacja w guzach a w zdrowej tkance
Dodanie fosforanów do białek (fosforylacja) to bardzo ważny proces dla ludzkiej biologii. Odpowiada on za regulację białek. Jest mediatorem transmisji wszelkiego rodzaju sygnałów w komórkach i pomiędzy nimi. Kinazy, enzymy będące katalizatorami fosforylacji, stanowią cele terapeutyczne w przypadku kilku ważnych chorób, w tym nowotworów. Finansowany przez UE projekt TOPAS planuje usprawnić proces diagnozowania nowotworów oraz proces leczenia poprzez katalogowanie poddanych fosforylacji białek w guzach. Zbadanie sposobu, w jaki inhibitory kinazy modulują ten „fosfoproteom”, rzuci światło na mechanizmy komórkowe działania przeciwnowotworowych inhibitorów kinazy. Możliwe zastosowania obejmują opracowanie ulepszonych leków przeciwnowotworowych oraz poprawę diagnostyki.
Cel
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.
Dziedzina nauki
Program(-y)
Temat(-y)
System finansowania
ERC-ADG - Advanced GrantInstytucja przyjmująca
80333 Muenchen
Niemcy