2023 Mentored Investigator Grant

Project summary

Epithelial ovarian cancer is the most lethal gynecological malignancy and high-grade serous ovarian carcinoma (HGSOC) is the most prevalent histosubtype. Approximately 20% of HGSOCs have overexpression of cyclin E. Cyclin E-high HGSOCs have a low response rate to current and emerging standard-of-care therapies such as poly (ADP-Ribose) polymerase inhibitors (PARPi) in part due to homologous recombination proficiency. Therefore, the long-term goal of this proposal is to develop novel therapeutics for cyclin E-high HGSOC patients by overcoming homologous recombination proficiency. Worse survival of cyclin E-high patients is due in part to the fact that these tumors are proficient in homologous recombination. Patients with Homologous recombination-deficient tumors typically respond better to both platinum-based and PARPi therapies. My preliminary data suggest that upregulation of wildtype Isocitrate dehydrogenase in cyclin E-high cells leads to increased alpha ketoglutarate levels. Alpha ketoglutarate is a co-factor for many histone demethylases. Increased levels of IDH1 lead to an increase in alpha ketoglutarate abundance, which decreases histone methylation of three specific histone marks required for the promotion of non-homologous recombination. Inhibition of IDH1 would increase the methylation of these histone marks, leading to decreased homologous recombination and increased non-homologous recombination, which would sensitize cells to PARP inhibitor therapies.

This grant was made possible in part by a generous donation from The Donald R. and Esther Simon Foundation.