Harnessing vulnerabilities at SAGA in MYC-driven cancer

Several types of cancers, including pediatric leukemia and neuroblastoma, a childhood nerve tumor, depend on the protein MYC, which is known for its potential to induce tumor growth. The gene MYC is a so-called proto-oncogene, which means that it has normal functions in the regulation of cell growth, but can cause cancer when overly activated. Despite enormous efforts, strategies to inhibit MYC in the context of cancer are still in their infancy. In this project we aim at inactivating the oncogenic activity of MYC by harnessing its co-factor SAGA. SAGA is a large protein complex comprising 20 components that affects the expression and activity of MYC. The idea for this project was triggered by preliminary scientific results showing that when two specific SAGA components are depleted in mouse embryonic stem cells, binding of MYC at its target genes is impaired. We speculate that the same could apply to cancer cells, particularly to those which are MYC-addicted, like the abovementioned childhood cancers. We expect to find novel vulnerabilities of MYC-addicted cancers within at least one or more of the 20 components of SAGA. To reach this goal, we will use a comprehensive three-step methodological approach that can be compared with the dismantling of a car engine: First, we screen for genetic mutations in all 20 parts of the car engine, i.e. SAGA. We anticipate to find at least one or two engine parts that are particularly promising. Second, we study the performance, the chromatin function, of such engine and see what happens when we remove each of the 20 mechanical parts individually. And finally we will look at how this big machine of proteins comes together and how the assembly of the engine can be blocked. This step includes tests, whether certain drugs, so-called small molecules are able to prevent the assembly of SAGA, and could thus be of use as potential therapy against MYC-driven cancers.

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