It has long been known that increased ribosome biogenesis is a hallmark of malignancy, while perturbed ribosome biogenesis has been observed in diseases such as Diamond Blackfan Anemia (DBA). The nucleolus is a key site for ribosome biogenesis, but more recently it has been shown to have other roles, including its ability to act as a cellular stress sensor, and initiate signalling programs within the cell that leads to downstream cellular events such as apoptosis, cell cycle arrest and senescence. This can be dependent on, or independent of p53, depending on the cell type. However, this process still remains to be understood and much detail is lacking.
Using our cellular model of perturbed ribosome biogenesis, we have successfully performed compound screens of 4169 known or clinically used compounds, to determine what modulates the p53-dependent nucleolar stress response. In particular, we are interested in drugs that suppress the p53 response (which could also be potential therapeutic treatments for DBA) and those that enhance the p53 response, which we would potentially be able to use in combination with other agents that induce nucleolar stress (e.g. CX-5461) to enhance the treatment of cancers (e.g. haematological malignancies). We are currently validating a number of compounds that have come out of the screen, and are further investigating how they are modulating this response using in vitro models of cancer, with a view to testing these compounds in vivo.