A preclinical study combining the DNA repair inhibitor Dbait with radiotherapy for the treatment of melanoma.
Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of "palliative" RT (10 × 3 Gy) or "radical" RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the "palliative" protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the "radical" protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial).
Institut Curie, Centre de Recherche, Orsay, France ; UMR3347, Centre National de la Recherche Scientifique, Orsay, France ; U1021, Institut National de la Santé et de la Recherche Médicale, Orsay, France ; Université Paris Sud, Orsay, France ; Clermont Université, Université d'Auvergne, EA7283 CREaT, Clermont-Ferrand, France ; Radiotherapy Department, Centre Jean Perrin, Clermont-Ferrand, France.
Julian
J
Biau
Institut Curie, Centre de Recherche, Orsay, France ; DNA Therapeutics, Evry, France.
Flavien
F
Devun
Institut Curie, Centre de Recherche, Orsay, France ; UMR3347, Centre National de la Recherche Scientifique, Orsay, France ; U1021, Institut National de la Santé et de la Recherche Médicale, Orsay, France ; Université Paris Sud, Orsay, France ; DNA Therapeutics, Evry, France.
Wael
W
Jdey
Institut Curie, Centre de Recherche, Orsay, France ; UMR3347, Centre National de la Recherche Scientifique, Orsay, France ; U1021, Institut National de la Santé et de la Recherche Médicale, Orsay, France ; Université Paris Sud, Orsay, France ; DNA Therapeutics, Evry, France.
Ewa
E
Kotula
Institut Curie, Centre de Recherche, Orsay, France ; DNA Therapeutics, Evry, France.
Maria
M
Quanz
Clermont Université, Université d'Auvergne, EA7283 CREaT, Clermont-Ferrand, France ; Radiotherapy Department, Centre Jean Perrin, Clermont-Ferrand, France.
Emmanuel
E
Chautard
DNA Therapeutics, Evry, France.
Mano
M
Sayarath
DNA Therapeutics, Evry, France.
Jian-Sheng
JS
Sun
Clermont Université, Université d'Auvergne, EA7283 CREaT, Clermont-Ferrand, France ; Radiotherapy Department, Centre Jean Perrin, Clermont-Ferrand, France.
Pierre
P
Verrelle
Institut Curie, Centre de Recherche, Orsay, France ; UMR3347, Centre National de la Recherche Scientifique, Orsay, France ; U1021, Institut National de la Santé et de la Recherche Médicale, Orsay, France ; Université Paris Sud, Orsay, France.
Marie
M
Dutreix
D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D003854:Deoxyribonucleotides / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy*; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D003854:Deoxyribonucleotides; D011838:Radiation-Sensitizing Agents
DNA-PK, DNA-dependent kinase; DSB, double-strand break; PARP, poly-adenyl-ribose polymerase; RT, radiation therapy; SSB, single-strand break; TGD, tumor growth delay