Project 460713

Senescence is an anticancer response that involves loss of proliferation and secretion of pro-inflammatory mediators that engage the immune system for the clearance of senescent cells. Senescence is normally induced by oncogenic stimuli in normal cells. Tumors arise when the signaling pathways that link oncogenes to senescence are disabled. However, tumors conserve the ability to undergo senescence a process that can be reactivated by certain chemotherapeutic agents. There is a lot of interest to create new anticancer therapies based on senescence for two reasons. First, senescent cells can be eliminated by the immune system, suggesting that pro-senescence agents can be combined with immunotherapy. Second, there are drugs known as senolytics that specifically kill senescent cells and can be combined with pro-senescence agents in a one-two punch anticancer therapy. In this proposal, we will obtain critical insights into the mechanisms of senescence and in particular how the process targets ribosome biogenesis. Ribosomes are the machines that make proteins and cancer cells have an increased requirement for them. We will demonstrate that targeting ribosome biogenesis is a powerful way to trigger senescence selectively in cancer cells. These senescent cancer cells can be killed by both known and new senolytics we have identified. Although we expect that this approach will be generally applicable to all cancers, we focus our proposal on pancreatic ductal adenocarcinoma given the high fatality rate and the lack of efficient treatments for this cancer. Overall this project will provide both new knowledge and reagents to investigate senescence as an anticancer mechanism as well as a proof of concept for a one-two punch anticancer therapy using senescence-inducing drugs and senolytics.