Scientific background of siDNA
Cancer treatment mainly consists of surgery wherever possible, chemotherapy and radiotherapy. Combined radio- and chemotherapies can increase the likelihood of success but are limited by their cumulative side effects. Molecular therapies for cancer treatment have emerged in the last decade, such as: monoclonal antibodies targeting the cell membrane receptors, inhibitors of tyrosine kinase receptor or other kinases involved in signal transduction involved in cell proliferation, pro-apoptotic and immunostimulating agents, etc. As cytostatic agents, their monotherapy regimen is rarely of sufficient clinical benefit. Synergistic outcomes are often obtained by their combination with chemo- or radiotherapy.
Most traditional cancer treatments are cytotoxic, and directly or indirectly cause DNA damages in the treated cells, which ultimately lead to their death. Their therapeutic action targets on the proliferating feature of tumor cells. However, several intrinsic and acquired resistances of tumor to these treatments are, at least in part, due to the tumor cells’ efficient DNA repair activities.
Instead of targeting a key gene/protein whatever its biological importance and clinical relevance, the innovative molecular therapy must deal with one or several key pathways as a global target, in conjunction with conventional therapies, so as to reach the most efficient cancer treatment.
siDNA concept & technology: rationale
siDNA (signal interfering DNA) technology is a paradigm-shift, different to all existing molecular therapies. It was conceived to target globally DNA lesions sensing, signaling and repair pathways in order to disable cancers’ defense to existing treatments. The siDNA, applied to the DSB repair processes, named Dbait (which stands for DSB bait). It consists of introducing short modified DNA molecules mimicking double strand breaks (DSB) into cells that up till then could efficiently repair DSB and thus survive. Antitumor efficacy of Dbait in association with radiotherapy (RT) or chemotherapy (CT) is explained by the fact that Dbait molecules trap the initial DSB sensing complexes, jam downstream repair signaling, disorganize subsequently all DSB repair systems (both Non Homologous End Joining and Homologous Recombination pathways), and finally inhibit DSB repair (please refer to the Publication section for more details). Ultimately, the cancer cells can no more escape their death.
This paradigm-shift siDNA concept has two key differences to the previous molecular therapy:
it doesn’t target to a specific gene/protein, but to a multi-gene/protein complex;
it doesn’t inhibit a specific gene/protein, but it jams relevant cascade of signal pathway.
It is the most recent breakthrough, based on a unique pathway-targeted/ mechanism-oriented approach. As such, siDNA technology exploits a new field beyond gene/protein-targeting approaches, and opens the era of supra-molecular therapy.