Targeting Ribosomal Function to Overcome Chemoresistance in Ovarian Cancer

Project summary

High grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. The standard of care for women with HGSOC is cytoreductive surgery followed by chemotherapy. Despite aggressive treatment strategies, a majority of patients with high grade HGSOC relapse. Chemotherapeutic agents target the fast-dividing cancer cells; therefore, slow-growing cells are not affected by chemotherapy. Accumulation of such slow-growing cancer cells can potentially cause resistance. The slow-growing cancer cells have high levels of stress tolerance and thus the pathways that control stress tolerance play a crucial role in chemotherapy resistance.

We recently discovered that HGSOC cells have high levels of a specific type of protein modification that controls protein synthesis and stress responses. In the studies proposed here we will follow up on these observations by exploring how this protein modification changes the mechanisms that control protein synthesis and stress responses in the context of chemotherapy.

We will also test whether blocking this protein modification will improve responses to chemotherapy in HGSOC. Successful completion of the proposed studies will shed light on new mechanisms of chemotherapy resistance and test new therapeutic agents to increase the sensitivity of chemotherapy. These studies have a potential to improve treatment outcomes for women with HGSOC.

This grant was made possible in part by a generous donation from the Melitta S. and Joan M. Pick Charitable Trust.