Next-Generation TOP1 Inhibition To Treat Ovarian Cancer

In this research project, investigators in the Mayo Clinic Ovarian Cancer SPORE are assessing DNA topoisomerase I (TOP1) inhibitors to treat ovarian cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors have been a major advance for women whose ovarian cancers carry mutations in BRCA1, BRCA2 or other genes involved in homologous recombination (HR) repair. However, the response to PARP inhibitors is much more limited when ovarian cancer has relapsed during PARP inhibitor treatment or when the cancer lacks HR interruption.

DNA topoisomerase I is the target of topotecan, which was approved by the U.S. Food and Drug Administration (FDA) for relapsed ovarian cancer in 1997. Laboratory evidence suggests that TOP1 inhibitors are more active if they are administered at low doses for prolonged periods of time, but that approach has been difficult to implement.

Four new targeted or sustained-release TOP1 inhibitor formulations recently have entered clinical testing.

This project builds on our team's previous results, which showed:

• TOP1 inhibitors can still exhibit anti-cancer effects when ovarian cancer cell lines and patient-derived xenografts become resistant to PARP inhibitors.
• This anti-cancer activity can be enhanced by adding DNA repair modulating agents, such as PARP inhibitors and ATR inhibitors.

Our researchers are conducting preclinical studies to better understand determinants of TOP1 inhibitor sensitivity, including a phase 2 clinical trial of one of the new generations of TOP1 inhibitors in ovarian cancer.