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.
Dr. Arun Kanakkanthara is an Assistant Professor in the Division of Oncology Research and The Department of Molecular Pharmacology and Experimental Therapeutics at Mayo Clinic. He completed his Ph.D. in Cancer Biology from the Victoria University of Wellington, New Zealand. Prior to his current position, Dr Kanakkanthara pursued his postdoctoral training in the labs of Dr Jan van Deursen and Dr Larry Karnitz at Mayo Clinic. One aspect of his current research focuses on understanding the metabolic remodeling and associated vulnerabilities/dependencies in ovarian cancer. Another area of his work focuses on understanding the mechanisms underlying the resistance to PARP inhibitors in ovarian cancer. Through his research, Dr. Kanakkanthara works to i) better understand the causes of metabolic abnormalities, with the ultimate goal of creating individualized therapy for patients with ovarian cancer, and ii) identify and develop novel therapeutic strategies to overcome PARP inhibitor resistance in ovarian cancer. He has received research awards from the Foundation for Women's Cancer and Mayo Clinic Ovarian Cancer SPORE.