title: [Dbait: An innovative concept to inhibit DNA repair and treat cancer].
abstract: The ability of cancer cells to recognize damage and initiate DNA repair is an important mechanism for therapeutic resistance. The use of inhibitors of DNA damage repair or signaling pathways appears to provide a unique opportunity for targeting genetic differences between tumor and normal cells. In this review, we firstly describe the main DNA lesions induced by the different treatments and the pathways involved in their repair. Then we review the mechanism of action and applications of an innovative DNA repair inhibitor: Dbait (and its clinical form DT01). Dbait/DT01 consists of 32 bp deoxyribonucleotides forming an intramolecular DNA double helix that mimics DNA lesions. They act as a bait for DNA damage signaling enzymes, the polyadenyl-ribose polymerase (PARP), and the DNA-dependent kinase (DNA-PK), inducing a "false" DNA damage signal and ultimately inhibiting recruitment at the damage site of many proteins involved in double-strand break and single-strand break repair pathways. Preclinical studies have demonstrated the capacity of Dbait/DT01 to improve the efficiency of (i) chemotherapy in colorectal cancer or hepatocellular carcinoma models, (ii) radiofrequency ablative in colorectal cancer liver metastases models, and (iii) radiotherapy in xenografted mice with head & neck squamous cell carcinoma, glioblastoma and melanoma. Following this good preclinical results, we performed a first-in-human phase 1-2a study evaluating the safety and efficacy of the combination of DT01 with radiotherapy for the treatment of skin metastases of melanoma. Twenty-three patients were included. No dose-limiting toxicity was observed. An objective response was observed in 59% lesions, including 30% complete responses. This first promising clinical efficacy provides future potential interesting clinical development of Dbait/DT01 with various anticancer treatments.
authors.affiliation: Centre de recherche, institut Curie, 91400 Orsay, France; Centre national de la recherche scientifique, UMR3347, Orsay, France; Institut national de la santé et de la recherche médicale, U1021, Orsay, France; Université Paris Sud, Orsay, France; Clermont université, université d'Auvergne, EA7283 CREaT, 63011 Clermont-Ferrand, France; Centre Jean-Perrin, département de radiothérapie, 58, rue Montalembert, 63011 Clermont-Ferrand, France. Electronic address: julian.biau@cjp.fr.
authors.forename: Julian
authors.initials: J
authors.lastname: Biau
authors.affiliation: Centre de recherche, institut Curie, 91400 Orsay, France; DNA Therapeutics, 91000 Evry, France.
authors.forename: Flavien
authors.initials: F
authors.lastname: Devun
authors.affiliation: Centre de recherche, institut Curie, 91400 Orsay, France; Clermont université, université d'Auvergne, EA7283 CREaT, 63011 Clermont-Ferrand, France; Centre Jean-Perrin, département de radiothérapie, 58, rue Montalembert, 63011 Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verrelle
authors.affiliation: Centre de recherche, institut Curie, 91400 Orsay, France; Centre national de la recherche scientifique, UMR3347, Orsay, France; Institut national de la santé et de la recherche médicale, U1021, Orsay, France; Université Paris Sud, Orsay, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Dutreix
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017115:Catheter Ablation; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011878:Radiotherapy; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases
keywords: DNA repair inhibition; DT01; Dbait; Inhibition réparation ADN