High-grade serous ovarian cancer (HGSOC) remains the deadliest form of ovarian cancer, in part because most patients develop recurrent disease that is resistant to standard treatment, including platinum therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have recently been approved as an important therapy for HGSOCs, especially for HGSOCs with defects in homologous recombination (HR) DNA repair due to mutations in BRCA1 or BRCA2. However, over 70% HGSOCs that initially respond to PARPis later develop resistant disease. Unfortunately, the underlying mechanisms of PARPi resistance are poorly understood. This project is designed to understand acquired PARPi resistance mechanisms and associated therapeutic vulnerabilities in HR-deficient HGSOCs. My preliminary studies show that HR-defective HGSOC cell lines and patient derived xenograft (PDX) mouse models that have developed resistance to PARPis have high levels of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1). Accordingly, my proposed studies aim to explore the roles and regulation of NMNAT1 in PARPi-resistant HGSOC cells and to test a novel therapeutic strategy that exploits a metabolic dependency associated with the NMNAT1 upregulation in the resistant cells. This research will reveal a novel mechanism by which HGSOC acquire resistance to PARPis and will provide important insights into a new therapeutic option for targeting PARPi-resistant HGSOCs.
|Effective start/end date||1/1/21 → 12/31/23|
- Ovarian Cancer Research Alliance: $150,000.00
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