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 such processes as replication and transcription. This enzyme is also the target of the anti-cancer drugs irinotecan, topotecan, MM398, PLX038 and CBX-12, along with a growing number of antibody-drug conjugates, such as trastuzumab deruxtecan and sacituzumab govitecan. Collectively, these agents are active in a variety of solid tumors, including cancers of the breast, colon, pancreas, lung, stomach 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. To facilitate these studies, our team recently developed a first-in-class antibody that specifically recognizes covalent topoisomerase I-DNA complexes. Using this antibody to covalent topoisomerase I-DNA complexes, we recently contributed to studies demonstrating the role of several proteases, including SPRTN and FAM111A, in DNA-protein crosslink repair.
This unique reagent is being applied in preclinical and clinical studies to determine whether the formation and repair 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're now investigating the possible beneficial effects of combining ATR inhibitors with topoisomerase I poisons in preclinical cancer models and clinical trials.