Cancer is a generic term for a group of diseases characterized by the uncontrolled growth and spread of cells with abnormal proliferating activity. Most of the anticancer drugs currently used in the clinic trigger DNA damage that ultimately lead to cancer cell death. As an alternative to direct inducer of DNA strand breaks, the non-covalent small-molecule stabilization of alternative nucleic acid structures is emerging as a promising way to create DNA damage. One of such non-B DNA structures is the three-way DNA junction (TWJ) that might fold both upstream and downstream of the replication fork. The stabilization of TWJ by small molecules can result in replication-associated DSB and therefore opens a promising avenue to induce replicative stress in a highly cancer-specific manner. The project STARFISH DNA (for "Stalling the Replication Fork via the Impedimental Stabilization of Higher-order DNAs") aims at identifying a series of compounds capable of creating DNA damage through three-way junction stabilization. Our goal is two-fold, using them to fight against cancers either as standalone therapeutics or in combination with established drugs that disrupt cancer DNA damage response in a synergistic manner. A particular attention will be paid to elucidate the molecular basis of the cellular dysregulations triggered by the most promising TWJ-interacting candidates, to better understand the DNA damage-related cellular events that underlie their anticancer activity.
Principal Investigator: Dr David Monchaud