Cellular Responses to DNA Damage Induced by Topoisomerase Poisons

The Anticancer Drug Action Lab is studying cellular responses to DNA damage induced by topoisomerase poisons.

DNA topoisomerase I is an abundant nuclear enzyme that adjusts the torsional strain on DNA during processes such as replication and transcription. This enzyme is also the target of the anticancer drugs irinotecan and topotecan, which are active in a variety of solid tumors, including cancers of the colon, pancreas, lung and ovary.

Studies in Dr. Kaufmann's lab are designed to improve the effectiveness of these agents.

In particular, our research team is examining factors that potentially affect the ability of these drugs to inhibit topoisomerase I (drug uptake and posttranslational modifications of topoisomerase I). We are also studying cellular responses to drug-induced trapping of covalent topoisomerase I-DNA complexes.

To facilitate these studies, our team recently developed a first-in-class antibody that specifically recognizes covalent topoisomerase I-DNA complexes.

This unique reagent is being applied in preclinical and clinical studies to determine whether the stabilization of drug-induced covalent topoisomerase I-DNA complexes varies from tumor to tumor and whether this variation correlates with tumor sensitivity.

Our lab's earlier studies showed that inactivation of the ATR/Chk1 pathway sensitizes cells to killing by this class of agents. Building on these results, we are also currently investigating the possible beneficial effects of combining ATR or Chk1 inhibitors with topoisomerase I poisons in preclinical cancer models.