Cancer continues to claim the lives of millions of patients every year (9.6 million deaths in 2018) despite the recent advances in cancer therapeutics. For some cancers, the 5-year survival rates are over 90% for patients (prostate, skin cancers) while others have far lower survival rates (20% for pancreatic, liver or lung cancers). This highlights the need for new therapeutic strategies, either deviating from classical anticancer drug regiments or exploiting them in an alternative manner.
The panoply of treatments provided to physicians and patients includes radiotherapy, immunotherapy and chemotherapy. The latter includes anticancer drugs the bulk of which targets DNA. This approach aims at creating DNA damage to cancer cells, the cancer-versus-healthy cells specificity relying on the poorest ability of cancer cells to manage DNA damage properly as compared to healthy cells. An alternative to irreversibly damage DNA is to stabilize unusual DNA structures that encompass all DNA structures that deviate from the canonical DNA double helix described by Watson & Crick. Their formation is promoted by DNA transactions (transcription, replication) due to local strand separation and DNA supercoiling related to the DNA/RNA polymerase motion along the genomic duplex-DNA. These unusual DNA structures form topological hindrances to replication and transcription machineries that equally threatens genetic integrity.
The reliability of this approach has already been demonstrated by the wealth of data collected over the past 2 decades with the four-stranded DNA structure named G-quadruplex-DNA. In the STARFISH DNA project (for Stalling the Replication Fork via the Impedimental Stabilization of Higher-order DNAs), we focus our attention on another unusual DNA structure, the three-way DNA junction (TWJ). Our aim was to demonstrate that the non-covalent stabilization of TWJ by specific small molecules (TWJ-ligands) does create roadblocks to polymerase processivity, thereby triggering DNA damage that eventually lead to cancer cell death. We selected TWJ as genetic targets since the ligand binding site is more structurally defined within a TWJ than in a G-quadruplex, making their targeting possibly more specific.
This 2-year multidisciplinary scientific program, performed in collaboration with Dr. Anton Granzhan (Institut Curie, Orsay FR) and Dr. Sébastien Britton (Institute of Pharmacology and Structural Biology, Toulouse, FR) has been undoubtedly successful given that we have validated all critical steps towards the development of a new class of anticancer agents. We have indeed screened chemical libraries to identify TWJ ligands, then further characterized the capability of the most promising candidates to interact with TWJ in vitro, prior to assess their antiproliferative activities in breast cancer cells, as standalone agents or included in drug combinations. Collectively, this program has led to the identification of new chemical weapons to fight against cancers that act according to an innovative strategy.
