Enhancing Existing Cancer Chemotherapies by Inhibition of WRN and BLM Helicases

Many existing cancer chemotherapeutic agents generate DNA damage that interferes with replication. These agents preferentially kill tumor cells that are generally unable to delay replication due to dysfunction of their G1/S checkpoint pathways. However, it has recently become clear that cells also possess other DNA damage tolerance pathways that respond to replication-blocking events, facilitate completion of replication and permit cell survival. RecQ helicases, particularly the WRN and BLM proteins, have important roles in pathways responding to replication blockage. Thus, targeted inhibition of WRN and/or BLM function is a reasonable strategy for enhancing the efficacy of certain chemotherapeutic agents including topoisomerase inhibitors and platinum compounds that generate replication-blocking DNA damage. Our ultimate goal is to identify small molecule inhibitors of WRN- and/or BLM-related pathways for use in combination with existing chemotherapeutic agents to further enhance their preferential killing of tumor cells. To that end, here we propose to establish and implement a high- throughput assay for WRN and BLM helicase activity to screen small molecule libraries to identify compounds that specifically inhibit one or both enzymes. Promising inhibitors would be tested for their ability to sensitize killing by platinum compounds and topoisomerase inhibitors in tumor cells and, in future studies, would be subject to refinement by chemical synthesis and molecular modeling and eventual testing in animal models. Establishment of this paradigm provides a solid foundation for seeking broader funding to support our longer term goals--i.e., developing effective inhibitory compounds for use in combinatorial regimens for cancer treatment in human clinical trials