Treatment of cancer by systemic administration of Dbait molecules

1. A method of treating triple-negative breast cancer (TNBC) or chemoresistant lung cancer comprising the administration, by a parenteral systemic route selected from intraperitoneal and intravenous administration to a subject having a triple-negative breast cancer (TNBC) or chemoresistant lung cancer, a nucleic acid molecule of the following formula:

wherein N is a deoxynucleotide, n is an integer from 15 to 195, the underlined N refers to a nucleotide having or not a modified phosphodiester backbone, L′ is a linker, C is the molecule facilitating endocytosis selected from a lipophilic molecule or a ligand which targets cell receptor enabling receptor mediated endocytosis, L is a linker, m is an integer being 0 or 1 and p is 1;

wherein the nucleic acid is to be used without combined administration of any quinoline endosomolytic agent.

2. The method according to claim 1 , wherein the nucleic acid of formula (I) has one or several of the following features:

N is a deoxynucleotide selected from the group consisting of A (adenine), C (cytosine), T (thymine) and G (guanine) and selected so as to avoid occurrence of a CpG dinucleotide and to have less than 80% sequence identity to any gene in a human genome; and/or

the linked L′ is selected from the group consisting of hexaethyleneglycol, tetradeoxythymidylate (T4) and 1,19-bis(phospho)-8-hydraza-2-hydroxy-4-oxa-9-oxo-nonadecane; and/or

m is 1 and L is a carboxamido polyethylene glycol; and/or

C is selected from the group consisting of a cholesterol, single or double chain fatty acids and a ligand which targets cell receptor.

3. The method according to claim 1 , wherein the nucleic acid molecule has one of the following formulae:

wherein the underlined nucleotide refers to a nucleotide having or not a phosphorothioate or methylphosphonate backbone, the linked L′ is selected from the group consisting of hexaethyleneglycol, tetradeoxythymidylate (T4) and 1,19-bis(phospho)-8-hydraza-2-hydroxy-4-oxa-9-oxo-nonadecane; m is 1 and L is a carboxamido oligoethylene glycol, C is selected from the group consisting of dioleoyl, octadecyl, folic acid, tocopherol and cholesterol.

4. The method according to claim 1 , wherein the nucleic acid is

and

wherein the underlined nucleotide refers to a nucleotide having a phosphorothioate backbone, the linked L′ is 1,19-bis(phospho)-8-hydraza-2-hydroxy-4-oxa-9-oxo-nonadecane; m is 1 and L is a carboxamido tetraethylene glycol, C is cholesterol.

5. The method according to claim 1 , wherein the nucleic acid is to be administered by intravenous route.

6. The method according to claim 5 , wherein the nucleic acid is to be administered by injection, intravenous drip, bolus or pump.

7. The method according to claim 1 , wherein the TNBC is a platinum-resistant cancer.

8. The method according to claim 1 , wherein the nucleic acid is administered in combination with radiotherapy and/or chemotherapy.

9. The method according to claim 1 , wherein the nucleic acid is administered in combination with a DNA damaging agent.

10. The method according to claim 9 , wherein the DNA damaging agent is selected from the group consisting of an inhibitor of topoisomerases I or II, a DNA crosslinker, a DNA alkylating agent, an anti-metabolic agent and inhibitors of the mitotic spindles.

11. The method according to claim 1 , wherein the nucleic acid is to be used in combination with a platinum drug selected from the group consisting of oxaliplatin, carboplatin and cisplatin.

12. The method according to claim 2 , wherein L is carboxamido triethylene or tetraethylene glycol.

13. The method according to claim 2 , wherein C is selected from the group consisting of octadecyl, oleic acid, dioleoyl acid, stearic acid, tocopherol, cholesterol, folic acid, galactose, mannose, oligosaccharide of galactose and/or mannose, RGD, bombesin, integrin and transferrin.