WO2021148581A1

WO2021148581A1 - Novel dbait molecule and its use

Info

Publication number: WO2021148581A1
Application number: PCT/EP2021/051409
Authority: WO
Inventors: Christelle Zandanel
Original assignee: Onxeo
Priority date: 2020-01-22
Filing date: 2021-01-22
Publication date: 2021-07-29

Abstract

The present invention relates to a new DBait molecule, the composition comprising it and its uses.

Description

NOVEL DBAIT MOLECULE AND ITS USE

FIELD OF THE INVENTION

The present invention relates to the field of medicine, in particular oncology. Specifically, the present invention relates to a DBait molecule. BACKGROUND OF THE INVENTION

It is now well recognized that DNA repair is an important target for cancer therapy. Drugs targeting tumor DNA Damage Response (DDR), used in monotherapy or in combination with additional anti-cancer agents, represents actual potential treatment options for patients suffering from various types of cancer, in particular rare or resistant cancers. Dbait molecules, conjugated (co-Dbait) or not, are small synthetic hairpin nucleic acid molecules that mimic DNA double-strand breaks and therefore interfere, disorganize and/or block damage signaling and DNA repair. Dbait and CoDbait molecules are disclosed in patent applications WO2005/040378, WO2008/034866, WO2008/084087, WO2011/161075, WO2017/013237, WO2017/148976, WO2019/175132 and WO2020/188015. More particularly, AsiDNA™ is a synthetic cholesterol-conjugate 32-base pair double helix DNA currently in clinical trial. This first-in-class signal-interfering repair technology successfully achieved phase 1 trials in patients with advanced solid tumors, showing favorable safety profile with maximum tolerated dose not reached. AsiDNA™ induced the intratumoral activation of its DNA-PK target, confirming its mechanism of action. AsiDNA™ is currently under clinical trials for systemic (IV) administration in solid tumors, in combination with anti-cancer treatments.

However, some difficulties for synthetizing DBait molecules remain and improvements are still necessary.

SUMMARY OF THE PRESENT INVENTION

The present invention provides new DBait nucleic acid molecules for treating cancer, which target DNA repair pathways. More specifically, the new DBait nucleic acid molecules are able to recruit and activate both DNA-PK and PARP proteins. More specifically, the present invention relates to a DBait nucleic acid molecule comprising a double-stranded nucleic acid moiety, the 5'end of the first strand and the 3'end of the complementary strand being linked together by a loop; the double-stranded nucleic acid moiety having the following sequence

the loop being

-O-P(X)OH -O-{[(CH₂)₂-O]_g-P(X)OH-O}_rK-O-P(X)OH-O-{[(CH₂)₂-O]_h-P(X)OH-O-}_s (l) with r and s being independently an integer 0 or 1; g and h being independently an integer from 1 to 7 and the sum g + h being from 4 to 7; X being O or S; with K being

with i, j, k and I being independently an integer from 0 to 6, preferably from 1 to 3; and m being an integer from 0 to 10. In a specific aspect, the double-stranded nucleic acid moiety has the following sequence

wherein internucleotide linkages "s" refer to phosphorothioate internucleotide linkages. Optionally, r is 1, s is 0 and g is an integer from 5 to 7, preferably 6.

Optionally, i and j are 1 and k and I are both 1 or 2. Optionally, m is an integer between 4 and 6, preferably 5.

In a very specific aspect, the DBait nucleic acid molecule is OX409 as detailed above.

The present invention further relates to a pharmaceutical or veterinary composition comprising a Dbait nucleic acid molecule according to the present invention. Optionally, the pharmaceutical or veterinary composition may further comprise a therapeutic agent, in particular selected from a chemotherapeutic agent such as a DNA damaging antitumoral agent, a PARP inhibitor, a kinase inhibitor, a HDAC inhibitor, a KRAS inhibitor, an immunotherapeutic agent, a hormonal therapeutic agent or any combination thereof.

The present invention also relates to a Dbait nucleic acid molecule or a pharmaceutical composition according to the present invention for use as a drug, more specifically for use for treating a cancer. Optionally, the Dbait nucleic acid molecule or a pharmaceutical composition can be used in combination with radiotherapy, a chemotherapeutic agent such as a DNA damaging antitumoral agent, a PARP inhibitor, a kinase inhibitor, a HDAC inhibitor, a KRAS inhibitor, an immunotherapeutic agent, a hormonal therapeutic agent or any combination thereof. Optionally, the cancer is selected from leukemia, lymphoma, sarcoma, melanoma, and cancers of the head and neck, kidney, ovary, pancreas, prostate, thyroid, lung, esophagus, breast, bladder, brain, colorectum, liver, and cervix.

Optionally, the chemotherapeutic agent is selected from the group consisting of a platinum agent such as cisplatin, oxaliplatin and carboplatin, an alkylating agent, a camptothecin, a nitrogen mustard, an antibiotic, an antimetabolite, and a vinca alkaloid.

Optionally, the PARP inhibitor is selected from the group consisting of rucaparib (AG014699, PF- 01367338), olaparib (AZD2281), veliparib (ABT888), iniparib (BSI 201), niraparib (MK 4827), talazoparib (BMN673), AZD 2461, CEP 9722, E7016, INO-1001, LT-673, MP-124, NMS-P118, XAV939, analogs, derivatives or a mixture thereof.

Optionally, the kinase inhibitor is selected from the group consisting of an inhibitor targeting one or several targets selected in the list consisting of EGFR family, ALK, B-Raf, MEK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, IGF1R, c-Met, JAK family, PDGFR α and β, RET, AXL, c-KIT, TrkA, TrkB, TrkC, ROS1, BTK and Syk, more preferably selected from the group consisting of gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS N° 1421373-98-9), poziotinib, WZ4002, Crizotinib, entrectinib, ceritinib, alectinib, lorlatinib, TSR-011, CEP-37440, ensartinib, Vemurafenib, dabrafenib, regorafenib, PLX4720, Cobimetinib, Trametinib, Binimetinib, Selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733, Lenvatinib, Debio- 1347, dovitinib, BLU9931, Sorafenib, sunitinib, lestaurtinib, tandutinib, quizartinib, crenolanib, gilteritinib, ponatinib, ibrutinib, Linsitinib, NVP-AEW541, BMS-536924, AG-1024, GSK1838705A, BMS-754807, PQ 401, ZD3463, NT157, Picropodophyllin (PPP), Tivantinib, JNJ-38877605, PF- 04217903, foretinib (GSK 1363089), Merestinib, Ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, cerdulatinib, gandotinib, momelotinib, pacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, imatinib, pazopanib, Telatinib, bosutinib, nilotinib, cabozantinib, Bemcentinib, amuvatinib, gilteritinib (ASP2215), glesatinib (MGCD 265), SGI-7079, Larotrectinib, RXDX-102, altiratinib, LOXO-195, sitravatinib, TPX-0005, DS-6051b, fostamatinib, entospletinib and TAK-659.

Optionally, the KRAS inhibitor is selected from the group consisting of AMG 510 (Amgen/Carmot Therapeutics), MRTX-849 (Mirati Therapeutics), ARS-3248 / JNJ-74699157 (Johnson & Johnson/ Wellspring Biosciences), Compound B (Sanofi/X-Chem Pharmaceuticals), LY3499446 (Eli Lilly), ARS-853, ARS-1620, BI-2852, BI-1701963 (Boehringer Ingelheim), mRNA-5671 (Moderna Therapeutics), G12D inhibitor (Mirati), RAS(On)inhibitors (Revolution medicines) and BBP-454 (BridgeBio Pharma).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Synthesis schema for DBait32Hc and OX409.

Figure 2. Principle of the DNA-PK activity Assay.

Figure 3. OX409 is recognized by DNA-PK enzyme as a DSB. OX409 or Dbait32Hc-induced DNA- PK ATPase activity was monitored using the DNA-PK activity assay, with increasing doses of OX409 or of Dbait32Hc. Rates of ATP hydrolysis (Vmax) and Michaelis constant (Km) were calculated using GraphPadprism software.

Figure 4. OX409 induces PARP hyperactivation in tumor cells. Cells were treated for 24 hours with OX409 (50nM) or Dbait32Hc (50nM). DNA-PK activation was monitored by analysis of γH2AX, and PARP activation was analyzed by quantification of proteins PARylation by western blot assay.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention provides a novel DBait molecule being optimized for the synthesis. Accordingly, the present invention relates to: - a DBait nucleic acid molecule as described below; - a pharmaceutical composition comprising a DBait nucleic acid molecule as described below and a pharmaceutically acceptable carrier, in particular for use in the treatment of cancer; - a DBait nucleic acid molecule as described below for use as a drug, in particular for use in the treatment of cancer; - the use of a DBait nucleic acid molecule as described below for the manufacture of a drug, in particular for use in the treatment of cancer; - a method for treating a cancer in a patient in need thereof, comprising administering an effective amount of a DBait nucleic acid molecule as disclosed herein; - a pharmaceutical composition comprising a DBait nucleic acid molecule as described below, an additional therapeutic agent and a pharmaceutically acceptable carrier, in particular for use in the treatment of cancer; - a product or kit containing (a) a DBait nucleic acid molecule as disclosed below, and optionally (b) an additional therapeutic agent, as a combined preparation for simultaneous, separate or sequential use, in particular in the treatment of cancer; - a combined preparation which comprises (a) a DBait nucleic acid molecule as disclosed below, (b) an additional therapeutic agent as described below for simultaneous, separate or sequential use, in particular in the treatment of cancer; - a pharmaceutical composition comprising a DBait nucleic acid molecule as disclosed below, for the use in the treatment of cancer in combination with an additional therapeutic agent; - the use of a pharmaceutical composition comprising a DBait nucleic acid molecule as disclosed below for the manufacture of a medicament for the treatment of cancer in combination with an additional therapeutic agent; - a method for treating a cancer in a patient in need thereof, comprising administering an effective amount of (a) a DBait nucleic acid molecule as disclosed below, and (b) an effective amount of an additional therapeutic agent, simultaneously, separately or sequentially; - a method for treating a cancer in a patient in need thereof, comprising administering an effective amount of a pharmaceutical composition comprising a DBait nucleic acid molecule as disclosed herein, and an effective amount of an additional therapeutic agent simultaneously, separately or sequentially; - a method for increasing the efficiency of a treatment of a cancer with a therapeutic antitumor agent, or for enhancing tumor sensitivity to treatment of said therapeutic antitumor agent in a patient in need thereof, comprising administering an effective amount of a DBait nucleic acid molecule as disclosed below and an effective amount of said additional therapeutic agent, simultaneously, separately or sequentially. Whenever within this whole specification "treatment of a cancer" or the like is mentioned with reference to the pharmaceutical composition, kit, product, combined preparation and combinations of the invention, there is meant: a) a method for treating a cancer, said method comprising administering a pharmaceutical composition, kit, product, combined preparation and combinations of the invention to a patient in need of such treatment; b) a pharmaceutical composition, kit, product, combined preparation, and combinations of the invention for use in the treatment of a cancer; c) the use of a pharmaceutical composition, kit, product, combined preparation and combinations of the invention for the manufacture of a medicament for the treatment of a cancer; and/or d) a pharmaceutical composition, kit, product, combined preparation and combinations of the invention for use for the treatment of cancer, and optionally for increasing the efficiency of a treatment of a cancer with a therapeutic antitumor agent, or for enhancing tumor sensitivity to treatment with a therapeutic antitumor.

Within the context of the invention, the term "treatment" denotes curative, symptomatic, and preventive treatment. Pharmaceutical compositions, kits, products, combined preparations and combinations of the invention can be used in humans with existing cancer or tumor, including at early or late stages of progression of the cancer. The pharmaceutical compositions, kits, products, combined preparations, and combinations of the invention will not necessarily cure the patient who has the cancer but will delay, slow, or stabilise the progression or prevent further progression of the disease, improving thereby the patients' condition. In particular, the pharmaceutical compositions, kits, products, combined preparations and combinations of the invention reduce the development of tumors, reduce tumor burden, produce tumor regression in a mammalian host and/or prevent metastasis occurrence and cancer relapse. In treating the cancer, the pharmaceutical composition, kit, product, combined preparation and combinations of the invention is administered in a therapeutically effective amount.

The terms "kit", "product", "combined preparation" or "combination", as used herein, define especially a "kit-of-parts" in the sense that the combination partners (a) and (b), as defined above can be dosed independently or by use of different fixed combinations with distinct amounts of the combination partners (a) and (b), i.e. simultaneously or sequentially at different time points. The components of the kit-of-parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit-of-parts. The ratio of the total amounts of the combination partner (a) to the combination partner (b), to be administered can be varied. The combination partners (a) and (b) can be administered by the same route or by different routes.

In some embodiments, "combination therapy" is intended to embrace administration of therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of all these therapeutic agents, or at least two of the therapeutic agents concurrently, or in a substantially simultaneous manner.

The term "concomitantly" is used herein to refer to administration of two or more therapeutic agents, given in close enough temporal proximity where their individual therapeutic effects overlap in time. Accordingly, concurrent administration includes a dosing regimen when the administration of one or more agent(s) continues after discontinuing the administration of one or more other agent(s).

By "effective amount" it is meant the quantity of the Dbait in a pharmaceutical composition, kit, product, combined preparation and combination of the invention which prevents, removes or reduces the deleterious effects of cancer in mammals, including humans, alone or in combination with the other active ingredients in the pharmaceutical composition, kit, product, combined preparation and combination. It is understood that the administered dose may be adapted by those skilled in the art according to the patient, the pathology, the stage of the disease, the mode of administration, etc. The DBait molecule

The DBait nucleic acid molecule comprises a double-stranded nucleic acid moiety, the 5'end of the first strand and the B'end of the complementary strand being linked together by a loop; the double-stranded nucleic acid moiety having the following sequence

the loop being

-O-P(X)OH-O-{[(CH₂)₂-O]_g-P(X)OH-O}_rK-O-P(X)OH-O-{[(CH₂)₂-O]_h-P(X)OH-O-}_s (l) with r and s being independently an integer 0 or 1; g and h being independently an integer from 1 to 7 and the sum g + h being from 4 to 7; with X being O or S; with K being

with i, j, k and I being independently an integer from 0 to 6, preferably from 1 to 3; and m being an integer from 0 to 10.

The double-stranded nucleic acid moiety may comprise nucleotide(s) with a modified phosphodiester backbone, in particular in order to protect them from degradation. Preferably, the nucleotide(s) having a modified phosphodiester backbone are located at the free end of the double-stranded moiety of the nucleic acid molecule. In one aspect, 1, 2 or 3 internucleotidic linkages of the nucleotides located at the free end of the double-stranded moiety of the nucleic acid molecule have a modified phosphodiester backbone, optionally on one or the other strand, preferably on both strands. Alternatively, the DBait nucleic acid molecules may have a 3'-3' nucleotide linkage ora 3'-5' nucleotide linkage at the end of a strand. In a preferred embodiment, the modified phosphodiester backbone can be a phosphorothioate.

Accordingly, in one aspect, the DBait nucleic acid molecule has the following sequence

wherein internucleotide linkages "s" refer to phosphorothioate internucleotide linkages.

In one aspect, r is 1, s is 0 and g is an integer from 5 to 7, preferably 6. In another aspect, s is 1, r is 0 and h is an integer from 5 to 7, preferably 6.

In one aspect, i and j are 1 and k and I are both 1 or 2.

In one aspect, m is an integer between 4 and 6, preferably 5.

In one aspect, r is 1, s is 0 and g is an integer from 5 to 7, preferably 6; i and j are 1 and k and I are both 1 or 2; and m is an integer between 4 and 6, preferably 5. In a very particular aspect, r, i and j is 1, s is 0, g is 6, k and I is 2, and m is 5. In a specific aspect, the the DBait nucleic acid molecule is

OX409 molecule Combination with other therapeutic agents

The DBait nucleic acid molecule can be used in combination with at least one additional active ingredient formulated in separate pharmaceutical composition(s) or the pharmaceutical composition comprising the DBait nucleic acid molecule may further comprise at least one additional active ingredient. The additional active ingredient is a drug used for treating cancer. Optionally, the DBait nucleic acid molecule can be used in combination with a radiotherapy, a radioisotope therapy, a chemotherapeutic agent such as a DNA damaging antitumoral agent, a PARP inhibitor, a kinase inhibitor, a HDAC inhibitor, a KRAS inhibitor, an immunotherapeutic agent, a hormonal therapeutic agent or any combination thereof or any anti-cancer drug. As used herein, the term "antitumor chemotherapy" or "chemotherapy" refers to a cancer therapeutic treatment using chemical or biochemical substances, in particular using one or several antineoplastic agents. The term "hormonal therapy" refers to a cancer treatment having for purpose to block, add or remove hormones. For instance, in breast cancer, the female hormones estrogen and progesterone can promote the growth of some breast cancer cells. So in these patients, hormonal therapy is given to block estrogen and a non-exhaustive list commonly used drugs includes: Tamoxifen, Fareston, Arimidex, Aromasin, Femara, Zoladex/Lupron, Megace, and Halotestin. The term "immunotherapy" refers to a cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells.

Radiotherapy includes, but is not limited to, γ-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other radiotherapies include microwaves and UV-irradiation. Other approaches to radiation therapy are also contemplated in the present invention.

More specifically, the additional active ingredient can be more specifically selected from a chemotherapy, a PARP inhibitor, a kinase inhibitor, a HDAC inhibitor and a KRAS inhibitor. The chemotherapy is preferably a DNA-damaging anti-tumoral agent.

DNA-damaging anti-tumor agents:

The DNA-damaging antitumor agent is preferably 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. More specifically, the DNA-damaging anti-tumor agent can be selected from the group consisting of a platinum agent, an alkylating agent, a camptothecin, a nitrogen mustard, an antibiotic, an antimetabolite, and a vinca alkaloid.

Inhibitors of topoisomerases I and/or II include, but are not limited to, etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicine, anthracyclines such as doxorubicine, epirubicine, daunorubicine, idanrubicine and mitoxantrone. Inhibitors of Topoisomerase I and II include, but are not limited to, intoplicine.

DNA crosslinkers include, but are not limited to, a platinum agent selected from the group consisting of cisplatin, carboplatin and oxaliplatin. Anti-metabolic agents block the enzymes responsible for nucleic acid synthesis or become incorporated into DNA, which produces an incorrect genetic code and leads to apoptosis. Non- exhaustive examples thereof include, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, and more particularly Methotrexate, Floxuridine, Cytarabine, 6-Mercaptopurine, 6- Thioguanine, Fludarabine phosphate, Pentostatin, 5-fluorouracil, gemcitabine and capecitabine.

The DNA-damaging anti-tumoral agent can be alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes. Non-exhaustive examples thereof include Uracil mustard, Chlormethine, Cyclophosphamide (CYTOXAN(R)), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Fotemustine, cisplatin, carboplatin, oxaliplatin, thiotepa, Streptozocin, Dacarbazine, and Temozolomide.

Inhibitors of the mitotic spindles include, but are not limited to, paclitaxel, docetaxel, vinorelbine, larotaxel (also called XRP9881; Sanofi-Aventis; RPR 109881A (Bristol-Meyer-Squibb)), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol-Meyer-Squibb), BMS-275183 (Bristol-Meyer-Squibb), ortataxel (also called IDN 5109, BAY 59-8862 or SB-T- 101131 ; Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT-287 (TAPESTRY), PG- paclitaxel (also called CT-2103, PPX, paclitaxel poliglumex, paclitaxel polyglutamate or XyotaxTM), ABRAXANE^® (also called Nab-Paclitaxel ; ABRAXIS BIOSCIENCE), Tesetaxel (also called DJ-927), IDN 5390 (INDENA), Taxoprexin (also called docosahexanoic acid-paclitaxel ; PROTARGA), DHA-paclitaxel (also called Taxoprexin^®), and MAC-321 (WYETH). Also see the review of Hennenfent & Govindan (2006, Annals of Oncology, 17, 735-749).

Preferably, the DNA-damaging antitumor agent is a platinum agent such as cisplatin, oxaliplatin and carboplatin. In another preferred aspect, the DNA-damaging antitumor agent can be paclitaxel.

PARP Inhibitors:

Provided here are also PARP inhibitors useful in the methods described herein. PARP is meant Poly (ADP-ribose) polymerase. PARP catalyzes the conversion of b-nicotinamide adenine dinucleotide (NAD+) into nicotinamide and poly-ADP-ribose (PAR). PARP is a key molecule in the repair of DNA single-strand breaks (SSBs). As used herein, the term "PARP inhibitor" refers to any compound which has the ability to decrease the activity of a poly (ADP-ribose) polymerase (PARP). PARP inhibition relies mainly on two different mechanisms: (i) catalytic inhibition that acts mainly by inhibiting PARP enzyme activity and (ii) bound inhibition that traps PARP enzyme and prevents its release from the damage site. Bound inhibitors are more toxic to cells than catalytic inhibitors. PARP inhibitors according to the invention are preferably catalytic and/or bound inhibitors. Many PARP inhibitors are known and, thus, can be synthesized by known methods from starting materials that are known, may be available commercially, or may be prepared by methods described in the literature.

Examples of suitable PARP inhibitors according to the invention include, but are not limited to, olaparib (AZD-2281, 4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl)-4- fluorophenyl]methyl(2H)-phthalazin-l-one), veliparib (ABT-888, CAS 912444-00-9, 2-((fi)-2- methylpyrrolidin-2-yl)-IW-benzimidazole-4-carboxamide), CEP-8983 (ll-methoxy-4, 5,6,7- tetrahydro-IH-cyclopenta[a]pyrrolo[3,4-c]carbazole-l,3(2H)-dione) or a prodrug thereof (e.g. CEP- 9722), rucaparib (AG014699, PF-01367338, 8-Fluoro-2-{4-[(methylamino)methyl]phenyl}- l,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one), E7016 (GPI-21016, 10-((4-

Hydroxypiperidin-l-yl)methyl)chromeno-[4,3,2-de]phthalazin-3(2H)-one), talazoparib (BMN-673, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-IH-l,2,4-triazol-5-yl)-8,9-dihydro-2H- pyrido[4,3,2de]phthalazin-3(7H)-one), INO-1001 (4-phenoxy-3-pyrrolidin-l-yl-5-sulfamoyl- benzoic acid), KU0058684 (CAS 623578-11-0), niraparib (MK 4827, Merck & Co Inc), iniparib (BSI 201), iniparib-met (C-nitroso metabolite of Iniparib), CEP 9722 (Cephalon Inc), LT-673, MP-124, NMS-P118, XAV939 and AZD 2461. Additional PARP inhibitors are described for example in WO14201972, WO14201972, WO12141990, WO10091140, WO9524379, WO09155402, WO09046205, WO08146035, WO08015429, WO0191796, WO0042040, US2006004028, EP2604610, EP1802578, CN 104140426, CN 104003979, US060229351, US7041675, WO07041357, WO2003057699, US06444676, US20060229289, US20060063926, WO2006033006, WO2006033007, WO03051879, WO2004108723, WO2006066172, WO2006078503, US20070032489, WO2005023246, WO2005097750, WO2005123687, WO2005097750, US7087637, US6903101, WO20070011962, US20070015814, WO2006135873, UA20070072912, WO2006065392, WO2005012305, WO2005012305, EP412848, EP453210, EP454831, EP879820, EP879820, WO030805, WO03007959, US6989388, EP1212328, WO2006078711, US06426415, US06514983, EP1212328, US20040254372, US20050148575, US20060003987, US06635642, WO200116137, WO2004105700, WO03057145A2, WO2006078711, WO2002044157, US20056924284, WO2005112935, US20046828319, WO2005054201, WO2005054209, WO2005054210, WO2005058843, WO2006003146, WO2006003147, WO2006003148, WO2006003150, WO2006003146, WO2006003147,

UA20070072842, US05587384, US20060094743, WO2002094790, WO2004048339, EP1582520, US20060004028, WO2005108400, US6964960, WO20050080096, WO2006137510,

UA20070072841, WO2004087713, WO2006046035, WO2006008119, WO06008118, WO2006042638, US20060229289, US20060229351, WO2005023800, WO1991007404, WO2000042025, WO2004096779, US06426415, WO02068407, US06476048, WO2001090077, WO2001085687, WO2001085686, WO2001079184, WO2001057038, WO2001023390, WO01021615A1, WO2001016136, WO2001012199, WO95024379, WO200236576, WO2004080976, WO2007149451, WO2006110816, WO2007113596, WO2007138351, WO2007144652, WO2007144639, WO2007138351, WO2007144637.

In a preferred embodiment, the PARP inhibitor is selected from the group consisting of rucaparib (AG014699, PF-01367338), olaparib (AZD2281), veliparib (ABT888), iniparib (BSI 201), niraparib (MK 4827), talazoparib (BMN673), AZD 2461, CEP 9722, E7016, INO-1001, LT-673, MP-124, NMS- P118 and XAV939.

HDAC inhibitors:

The term "histone deacetylase" or "HDAC", as used herein, refers to an enzyme that removes acetyl groups from histones. There are currently 18 known HDACs, which are classified into four groups. Class I HDACs, includes HDACl-3 and HDAC8. Class II HDACs include HDAC4-7 and HDAC9- 10. Class III HDACs (also known as the sirtuins) include SIRT1-7. Class IV HDACs, which contains only HDAC11, has features of both Classes I and II HDACs.

The term "histone deacetylase inhibitor" or "HDACi" as used herein, refers to a compound natural or synthetic that inhibits histone deacetylase activity. There exists different classes of HDACi in function of their selectivity for their substrates divided in classical HDACi, selective class I HDACi and selective class II HDACi.

A "classical HDACi" (also known as pan-HDACi) refers thus to a compound natural or not which has the capability to inhibit the histone deacetylase activity independently of the class of HDACs. Therefore a classical HDACi is a non selective HDACi. By "non selective" it is meant that said compound inhibits the activity of classical HDACs (i.e. class I, II and IV) with a similar efficiency independently of the class of HDAC. Examples of classical HDACi include, but are not limited to, Belinostat (PDX-101), Vorinostat (SAHA) and Panobinostat (LBH-589). A "selective class I HDACi" is selective for class I HDACs (i.e. HDAC 1-3 and 8) as compared with class II HDACs (i.e. HDAC4-7, 9 and 10). By "selective" it is meant that selective class I HDACi inhibits class I HDACs at least 5-fold, preferably 10-fold, more preferably 25-fold, still preferably 100-fold higher than class II HDACs. Selectivity of HDACi for class I or class II HDACs may be determined according to previously described method (Kahn et al. 2008). Examples of selective class I HDACi include, but are not limited to, valproic acid (VPA), Romidepsin (FK-228) and Entinostat (MS-275).

A "selective class II HDACi" is selective for class II HDACs (i.e. HDAC4-7, 9 and 10) as compared with class I HDACs (i.e. HDAC 1-3 and 8). By "selective" it is meant that selective class II HDACi inhibits class II HDACs at least 5-fold, preferably 10-fold, more preferably 25-fold, still preferably 100-fold higher than class I HDACs. Examples of selective class II HDACi include, but are not limited to, tubacin and MC-1568 (aryloxopropenyl)pyrrolyl hydroxamate).

HDAC inhibition relies mainly on a mechanism based on the inhibition of the HDAC enzymatic activity which can be determined by a variety of methods well known by the skilled person. Usually, these methods comprise assessing the lysine deacetylase activity of HDAC enzymes using colorimetric HDAC assays. Commercial kits for such techniques are available (see for example, Histone Deacetylase (HDAC) Activity Assay Kit (Fluorometric) purchased from Abeam or Sigma- Aldrich). These methods are ideal for the determination of IC50 values of known or suspected HDAC inhibitors.

Many HDAC inhibitors are known and, thus, can be synthesized by known methods from starting materials that are known, may be available commercially, or may be prepared by methods used to prepare corresponding compounds in the literature.

A preferred class of HDAC inhibitors are hydroxamic acid inhibitors which are disclosed e. g. in WO 97/35990, US-A 5, 369, 108, US-A 5, 608, 108, US-A 5, 700, 811, WO 01/18171, WO 98/55449, WO 93/12075, WO 01/49290, WO 02/26696, WO 02/26703, JP 10182583, WO 99/12884, WO 01/38322, WO 01/70675, WO 02/46144, WO 02/22577 and WO 02/30879. All HD AC inhibitors disclosed in these publications are included herein by reference.

Particularly preferred are HDAC inhibitors are carbamic acid compounds comprising a sulfonamide linkage which are disclosed e. g. in WO 02/30879. Other HDAC inhibitors which can be included within the compositions of the present invention are cyclic peptide inhibitors, and here it can be referred e. g. to US-A 5,620, 953, US-A 5, 922, 837, WO 01/07042, WO 00/08048, WO 00/21979, WO 99/11659, WO 00/52033 and WO 02/0603. All HDAC inhibitors disclosed in these publications are included herein by reference.

Suitable HDAC inhibitors are also those which are based on a benzamide structure which are disclosed e. g. in Proc. Natl. Acad. Sci. USA (1999), 96: 4592-4597, but also in EP-A 847992, US 6, 174, 905, JP 11269140, JP 11335375, JP 11269146, EP 974576, WO 01/38322, WO 01/70675 and WO 01/34131. All HDAC inhibitors, which are disclosed in these documents, are included herein by reference.

The HDAC inhibitors may be used under any pharmaceutically acceptable form, including without limitation, their free form and their pharmaceutically acceptable salts or solvates.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable, preferably non-toxic, bases or acids including mineral or organic acids or organic or inorganic bases. Such salts are also known as acid addition and base addition salts." Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.

The term "solvate" refers to a molecular complex comprising the drug substance and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to a solvate comprising the drug substance and a stoichiometric or non-stoichiometric amount of water. More particularly, examples of suitable HDAC inhibitors according to the invention include, but are not limited to the compounds listed in Table 1 below: Table 1: Examples of HDAC inhibitors useful within the context of the invention

In a preferred embodiment, the HDAC inhibitor is selected from the group consisting of belinostat (PXD-101), vorinostat (SAHA), entinostat (MS-275) panabinostat (LBH-589), mocetinostat (MGCD010S), chidamide (HBI-8000) and romidepsin (FK-228).

KRAS inhibitors:

KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) belongs to RAS proteins (the four isoforms KRAS4A, KRAS4B, NRAS and HRAS encoded by three genes KRAS, NRAS and HRAS) acting as molecular switches that drive several key cellular processes such as cell growth, proliferation and survival. With about a third of all cancers driven by harmful mutations in the RAS family of genes, KRAS is the most frequently mutated oncogene in human tumors, causing tumor genesis and tumor maintenance. 20% of all solid tumors contain oncogenic KRAS mutations. In a particular aspect, the KRAS inhibitor is known to be associated with an acquired resistance during the cancertreatment. In a very particular aspect, the KRAS inhibitor is associated with the occurrence of persister cancer cells during a treatment of cancer with this KRAS inhibitor.

In one aspect, the KRAS inhibitor is a direct KRAS inhibitor selected from the group consisting of specific covalent KRAS inhibitors and multivalent small-molecule pan KRAS inhibitors.

In a particular aspect, KRAS inhibitor of the present invention is selected from the group consisting of AMG 510 (Amgen/Carmot Therapeutics), MRTX-849 (Mirati Therapeutics), ARS- S248/JNJ-74699157 (Johnson & Johnson/ Wellspring Biosciences), Compound B (Sanofi/X-Chem Pharmaceuticals), LY3499446 (Eli Lilly), ARS-853, ARS-1620, BI-2852, BI-1701963 (Boehringer Ingelheim), mRNA-5671 (Moderna Therapeutics), G12D inhibitor (Mirati), RAS(On)inhibitors (Revolution medicines) and BBP-454 (BridgeBio Pharma).

Optionally, the KRAS inhibitor is a KRASG12C inhibitor directly targeting and binding mutant KRASG12C protein.

Protein kinase inhibitors:

The kinase inhibitor of the present invention is a kinase inhibitor for treating cancer. In particular, the kinase can be a tyrosine kinase, a serine/threonine kinase or a kinase with dual specificity. In a particular aspect, the kinase inhibitor is known to be associated with an acquired resistance during the cancer treatment. In a very particular aspect, the kinase inhibitor is associated with the occurrence of persister cancer cells during a treatment of cancer with this kinase inhibitor.

The kinase inhibitors may target any one of the following kinases: EGFR family, ALK, B-Raf, MEK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, IGF1R, c-Met, JAK family, PDGFR α and β, RET, AXL, c-KIT, TrkA, TrkB, TrkC, ROS1, BTK and Syk.

In one aspect, the kinase inhibitor is an inhibitor targeting a receptor tyrosine kinase, especially one selected from the group consisting of EGFR family, ALK, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, RET, IGF1R, PDGFR α and β, c-KIT, FLT3, AXL, TrkA, TrkB, TrkC, and ROS1.

In a particular aspect, the kinase inhibitor is an inhibitor targeting a tyrosine kinase selected from the group consisting of EGFR, ALK, B-Raf, MEK, c-Met, JAK, PDGFR α and β, RET and BTK. For instance, a group of tyrosine kinases evolutionary and structurally related to ALK is RET, ROS1, AXL and Trk families kinases.

The kinase inhibitor is a small organic molecule. The term excludes biological macromolecules (e.g.; proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to 2000 Da, and most preferably up to about 1000 Da.

The kinase inhibitor may target EGFR (epidermal growth factor receptor), also called ErbB-1 and HER1 (see UniprotKB - P00533). The EGFR kinase inhibitors are well-known. For instance, reviews are published disclosing such EGFR kinase inhibitors (Expert Opinion on Therapeutic Patents Dec 2002, Vol. 12, No. 12, Pages 1903-1907; Kane, Expert Opinion on Therapeutic Patents Feb 2006, Vol. 16, No. 2, Pages 147-164; Traxler, Expert Opinion on Therapeutic Patents Dec 1998, Vol. 8, No. 12, Pages 1599-1625; Singh et al, Mini Rev Med Chem. 2016;16(14):1134-66; Cheng et al, Curr Med Chem. 2016;23(29):3343-3359; Milik et al, Eur J Med Chem. 2017 Dec 15;142:131-151.; Murtuza et al, Cancer Res. 2019 Feb 15;79(4):689-698; Tan et al, Onco Targets Ther. 2019 Jan 18;12:635-645; Roskoski, Pharmacol Res. 2019 Jan;139:395-411; Mountzios, Ann Transl Med. 2018 Apr;6(8):140; Tan et al, Mol Cancer. 2018 Feb 19;17(1):29), the disclosure of which being incorporated herein by reference. Patent applications also disclose EGFR kinase inhibitors, for instance and non-exhaustively WO19010295, WO19034075, WO18129645, WO18108064, WO18050052, WO18121758, WO18218963, WO17114383, WO17049992, WO17008761,

WO17015363, WO17016463, WO17117680, WO17205459, WO16112847, WO16054987, WO16070816, WO16079763, WO16125186, WO16123706, WO16050165, WO15081822, WO12167415, WO13138495, WO10129053, WO10076764, WO09143389, WO05065687, WO05018677, WO05027972, WO04011461, WO0134574, the disclosure of which being incorporated herein by reference. Specific examples of EGFR kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target ALK (Anaplastic lymphoma kinase, also known as ALK tyrosine kinase receptor or CD246; UniprotKB - Q9UM73). The ALK kinase inhibitors are well-known. For instance, reviews are published disclosing such ALK kinase inhibitors (Beardslee et al, J Adv Pract Oncol. 2018 Jan-Feb;9(l):94-101; Pacenta et al, Drug Des Devel Ther. 2018 Oct 23;12:3549-3561; Spagnuolo et al, Expert Opin Emerg Drugs. 2018 Sep;23(3):231-241; Peters et al, Curr Treat Options Oncol. 2018 May 28;19(7):37; Goldings et al, Mol Cancer. 2018 Feb 19;17(1):52; Karachaliou et al, Expert Opin Investig Drugs. 2017 Jun;26(6):713-722; Liu et al, Curr Med Chem. 2017;24(6):590-613; Crescenzo et al, Curr Opin Pharmacol. 2015 Aug;23:39-44; Sgambato et al, Expert Rev Anticancer Ther. 2018 Jan;18(l):71-80; Michellys et al, Bioorg Med Chem Lett. 2016 Feb 1;26(3):1090-1096; Straughan et al, Curr Drug Targets. 2016;17(6):739-45), the disclosure of which being incorporated herein by reference. Patent applications also disclose ALK kinase inhibitors, for instance and non-exhaustively WO04080980, WO05016894, WO05009389, WO09117097, WO09143389, WO09132202, WO10085597, WO10143664, WO11138751,

WO12037155, WO12017239, WO12023597, WO13013308, WO14193932, WO15031666, WO15127629, WO15180685, WO15194764, WO17076355, WO18001251, WO18044767,

WO18094134, WO18127184, the disclosure of which being incorporated herein by reference. Specific examples of ALK kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target B-Raf (Serine/threonine-protein kinase B-raf, also known as Proto-oncogene B-Raf, p94 or v-Raf murine sarcoma viral oncogene homolog B1; UniprotKB - P15056). The B-Raf kinase inhibitors are well-known. For instance, reviews are published disclosing such B-Raf kinase inhibitors (Tsai et al, PNAS February 26, 2008 105 (8) 3041-3046, Garnett et Marais, 2004 Cancer cell, Volume 6, Issue 4, Pages 313-319; Wilmott et al 2012, Cancer Therapy: Clinical, Volume 18, Issue 5; Fujimura et al, Expert Opin Investig Drugs. 2019 Feb;28(2):143-148, Trojaniello et al, Expert RevCIin Pharmacol. 2019 Mar;12(3):259-266; Kakadia et al, Onco Targets Ther. 2018 Oct 17;11:7095-7107; Roskoski, Pharmacol Res. 2018 Sep;135:239- 258; Eroglu et al, Ther Adv Med Oncol. 2016 Jan;8(l):48-56), the disclosure of which being incorporated herein by reference. Patent applications also disclose B-Raf kinase inhibitors, for instance and non-exhaustively WO14164648, WO14164648, WO14206343, WO13040515, WO11147764, WO11047238, WO11025968, WO11025951, WO11025938, WO11025965, WO11090738, WO09143389, WO09111280, WO09111279, WO09111278, WO09111277, WO08068507, WO08020203, WO07119055, WO07113558, WO07071963, WO07113557, WO06079791, WO06067446, WO06040568, WO06024836, WO06024834, WO06003378,

WO05123696, the disclosure of which being incorporated herein by reference. Specific examples of B-Raf kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target MEK (Mitogen-activated protein kinase kinase, also known as MAP2K, MP2K, MAPKK, MAPK/ERK kinase, JNK-activating kinase, c-Jun N-terminal kinase kinase (JNKK), Stress-activated protein kinase kinase (SAPKK) ; UniprotKB - Q02750 (MP2K1), P36507 (MP2K2), P46734 (MP2K3), P45985 (MP2K4), Q13163 (MP2K5), P52564 (MP2K6), 014733 (MP2K7)). Preferably, the kinase inhibitors target MEK-1 (also known as MAP2K1, MP2K1, MAPKK 1 or MKK1) and/or MEK-2 (also known as MAP2K2, MP2K2, MAPKK 2 or MKK2). Both MEK-1 and MEK-2 function specifically in the MAPK/ERK cascade. The MEK kinase inhibitors are well-known. For instance, reviews are published disclosing such MEK kinase inhibitors (Kakadia et aI, Onco Targets Ther. 2018 Oct 17;11:7095-7107; Steeb et aI, Eur J Cancer. 2018 Nov;103:41-51; Sarkisian and Davar, Drug Des Devel Ther. 2018 Aug 20;12:2553-2565; Roskoski, Pharmacol Res. 2018 Sep;135:239-258; Eroglu et aI, Ther Adv Med Oncol. 2016 Jan;8(l):48-56), the disclosure of which being incorporated herein by reference. Patent applications also disclose MEK kinase inhibitors, for instance and non-exhaustively WO15022662, WO15058589, WO14009319, WO14204263, WO13107283, WO13136249, WO13136254, WO12095505, WO12059041, WO11047238, WO11047055, WO11054828, WO10017051, WO10108652, WO10121646, WO10145197,

WO09129246, WO09018238, WO09153554, WO09018233, WO09013462, WO09093008,

WO08089459, WO07014011, WO07044515, WO07071951, WO07022529, WO07044084,

WO07088345, WO07121481, WO07123936, WO06011466, WO06011466, WO06056427,

WO06058752, WO06133417, WO05023251, WO05028426, WO05051906, WO05051300, WO05051301, WO05051302, WO05023759, WO04005284, WO03077855, WO03077914, WO02069960, WO0168619, WO0176570, WO0041994, WO0042022, WO0042003, WO0042002, WO0056706, WO0068201, WO9901426, the disclosure of which being incorporated herein by reference. Specific examples of MEK kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target FGFR (Fibroblast growth factor receptor; UniprotKB - P11362 (FGFR1), P21802 (FGFR2), P22607 (FGFR3), P22455 (FGFR4)). The FGFR kinase inhibitors are well- known. For instance, reviews are published disclosing such FGFR kinase inhibitors (Katoh, Int J Mol Med. 2016 Jul;38(l):3-15 ; Rizvi et Borad, J Gastrointest Oncol. 2016 Oct;7(5):789-796; Tan et aI, Onco Targets Ther. 2019 Jan 18;12:635-645, Shen et al, J Hematol Oncol. 2018 Sep 19;11(1):120; Porta et aI, Crit Rev Oncol Hematol. 2017 May;113:256-267; Cheng et al, Eur J Med Chem. 2017 Jan 27;126:476-490), the disclosure of which being incorporated herein by reference. Patent applications also disclose FGFR kinase inhibitors, for instance and non- exhaustively WO19034075, WO19034076, WO19001419, WO18028438, WO18049781,

WO18121650, WO18153373, WO18010514, WO17028816, WO17070708, WO16091849,

WO16134320, WO16054483, WO15059668, WO14007951, WO14026125, WO14129477,

WO14162039, WO14172644, WO13108809, WO13129369, WO13144339, WO13179033, WO13053983, WO12008563, WO12008564, WO12047699, WO09153592, WO08078091, WO08075068, WO06112479, WO04056822, the disclosure of which being incorporated herein by reference. Specific examples of FGFR kinase inhibitors are disclosed in the following table. The FGFR kinase inhibitor can be selective one or several FGFR family members, especially members selected from FGFR1, FGFR2, FGFR3 and FGFR4.

The kinase inhibitors may target FLT3 (Receptor-type tyrosine-protein kinase FLT3, also known as FL cytokine receptor, Fetal liver kinase-2 (FLK-2), Fms-like tyrosine kinase 3 (FLT-3), Stem cell tyrosine kinase 1 (STK-1) or CD antigen: CD135; UniprotKB - P36888). The FLT3 kinase inhibitors are well-known. For instance, reviews are published disclosing such FLT3 kinase inhibitors (Stone, Best Pract Res Clin Haematol. 2018 Dec;31(4):401-404; Wu et al, J Hematol Oncol. 2018 Dec 4;11(1):133; Short et al, Ther Adv Hematol. 2019 Feb 15;10:2040620719827310; Elshouryet al, Expert Rev Anticancer Ther. 2019 Mar;19(3):273-286; Zhi et al, Eur J Med Chem. 2018 Jul 15;155:303-315; Tiong IS, Wei AH, Genes Chromosomes Cancer. 2019 Mar 12, Gallogly et Lazarus, J Blood Med. 2016 Apr 19;7:73-83; Pitoia et Jerkovich, Drug Des Devel Ther. 2016 Mar 11;10:1119-31), the disclosure of which being incorporated herein by reference. Patent applications also disclose kinase inhibitors, for instance and non-exhaustively WO19034538,

WO17148440, WO15056683, WO13170671, WO13124869, WO13142382, WO13157540, WO11086085, WO09095399, WO09143389, WO08111441, WO08046802, WO06020145, WO06106437, WO06135719, the disclosure of which being incorporated herein by reference. Specific examples of FLT3 kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target IGF1R (Insulin-like growth factor 1 receptor also known as Insulin-like growth factor I receptor (IGF-I receptor) or CD antigen: CD221 ; UniprotKB - P08069 or C9J5X1). The IGF1R kinase inhibitors are well-known. For instance, reviews are published disclosing such IGF1R kinase inhibitors (Qu et al, Oncotarget. 2017 Apr 25;8(17):29501-29518; Chen et al, Curr Top Med Chem. 2017 Nov 20;17(28):3099-3130), the disclosure of which being incorporated herein by reference. Patent applications also disclose IGF1R kinase inhibitors, for instance and non-exhaustively WO16082713, WO08076415, WO08000922, WO08076143, WO07121279, WO07083017, WO07075554, WO06080450, WO05095399, WO05097800,

WO05037836, WO02092599, the disclosure of which being incorporated herein by reference. Specific examples of IGF1R kinase inhibitors are disclosed in the following table. The kinase inhibitors may target c-Met (Hepatocyte growth factor receptor, also known as HGF/SF receptor, Proto-oncogene c-Met, Scatter factor receptor or Tyrosine-protein kinase Met; UniprotKB - P08581). The c-Met kinase inhibitors are well-known. For instance, reviews are published disclosing such c-Met kinase inhibitors (Zhang et aI, Expert Opin Ther Pat. 2019 Jan;29(l):25-41; Gozdzik-Spychalska et aI, Curr Treat Options Oncol. 2014 Dec;15(4):670-82; Bahrami et al, J Cell Physiol. 2017 Oct;232(10):2657-2673; Zhang et al, Eur J Med Chem. 2016 Jan 27; 108:495-504; Qi et al, World J Gastroenterol. 2015 May 14;21(18):5445-53), the disclosure of which being incorporated herein by reference. Patent applications also disclose c-Met kinase inhibitors, for instance and non-exhaustively WO18153293, WO18187355, WO14000713, WO14032498, WO14067417, WO14180182, WO1307089, WO13107285, WO13149581, WO12006960, WO12015677, WO12034055, WO12048258, WO12075683, WO11039527,

WO11079142, WO11121223, WO11143646, WO11149878, WO10007317, WO10007316, WO10007318, WO10019899, WO10059668, WO10089508, WO10089509, WO09143389,

WO09143211, WO09056692, WO09093049, WO09068955, WO13013308, WO08023698, WO08008310, WO08102870, WO07036630, WO07066185, WO07023768, WO07002254, WO07002258, WO07111904, WO06104161, WO05082854, WO05082855, WO0160814 the disclosure of which being incorporated herein by reference. Specific examples of c-Met kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target JAK (Tyrosine-protein kinase JAK2, also known as Janus kinase 2; UniprotKB - 060674). The JAK kinase inhibitors are well-known. For instance, reviews are published disclosing such JAK kinase inhibitors (He et al, Expert Opin Ther Pat. 2019

Feb;29(2): 137-149; Hobbs et al, Hematol Oncol Clin North Am. 2017 Aug;31(4):613-626;

Senkevitch et Durum, Cytokine. 2017 Oct;98:33-41; Leroy et Constantinescu, Leukemia. 2017 May;31(5):1023-1038; Jin et al, Pathol Oncol Res. 2019 Jan 31), the disclosure of which being incorporated herein by reference. Patent applications also disclose JAK kinase inhibitors, for instance and non-exhaustively WO19034153, WO18215389, WO18215390, WO18204238, WO17006968, WO17079205, WO17091544, WO17097224, WO17129116, WO17140254,

WO17215630, WO16027195, WO16032209, WO16116025, WO16173484, WO16191524, WO16192563, WO15174376, WO15039612, WO14111037, WO14123167, WO14146492,

WO14186706, WO13091539, WO13188184, WO11076419, WO10085597, WO10051549, WO10083283, WO10135621, WO10142752, WO10149769, WO11003065, WO09132202, WO09143389, WO09062258, WO09114512, WO09145856, WO09155565, WO09155551, WO08047831, WO08109943, WO08116139, WO08157207, WO07070514, WO07084557,

WO07117494, WO07007919, WO06034116, WO06056399, WO06069080, WO05095400,

WO04058753, WO04041789, WO04041814, WO04041810, WO03101989, WO0152892, the disclosure of which being incorporated herein by reference. Specific examples of JAK kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target PDGFR (Platelet-derived growth factor receptor, also known as Platelet-derived growth factor receptor, CD140 antigen-like family member; UniprotKB - P16234 (PGFRA) P09619 (PGFRB)). The PDGFR kinase inhibitors are well-known. For instance, reviews are published disclosing such PDGFR kinase inhibitors (Roskoski, Pharmacol Res. 2018 Mar;129:65- 83; Andrick et Gandhi, Ann Pharmacother. 2017 Dec;51(12):1090-1098; Khalique et Banerjee, Expert Opin Investig Drugs. 2017 Sep;26(9):1073-1081; Miyamoto et al, Jpn J Clin Oncol. 2018 Jun 1;48(6):503-513; Gallogly et Lazarus, J Blood Med. 2016 Apr 19;7:73-83; Pitoia et Jerkovich, Drug Des Devel Ther. 2016 Mar 11;10:1119-31; Chen et Chen, Drug Des Devel Ther. 2015 Feb 9;9:773- 9), the disclosure of which being incorporated herein by reference. Patent applications also disclose PDGFR kinase inhibitors, for instance and non-exhaustively WO11119894, WO08016192, WO07004749, WO03077892, WO03077892, WO0164200, WO0125238, WO0172711,

WO0172758, WO9957117, and WO9928304, the disclosure of which being incorporated herein by reference. Specific examples of PDGFR kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target RET (Proto-oncogene tyrosine-protein kinase receptor Ret, also known as Cadherin family member 12 or Proto-oncogene c-Ret; UniprotKB - P07949). The RET kinase inhibitors are well-known. For instance, reviews are published disclosing such RET kinase inhibitors (Roskoski et Sadeghi-Nejad, Pharmacol Res. 2018 Feb;128:l-17; Zschabitz et Grüllich; Recent Results Cancer Res. 2018;211:187-198; Grüllich, Recent Results Cancer Res. 2018;211:67- 75; Pitoia et Jerkovich, Drug Des Devel Ther. 2016 Mar 11;10:1119-31), the disclosure of which being incorporated herein by reference. Patent applications also disclose RET kinase inhibitors, for instance and non-exhaustively WO18071454, WO18136663, WO18136661, WO18071447, WO18060714, WO18022761, WO18017983, WO17146116, WO17161269, WO17146116, WO17043550, WO17011776, WO17026718, WO14050781, WO07136103, WO06130673, the disclosure of which being incorporated herein by reference. Specific examples of RET kinase inhibitors are disclosed in the following table. The kinase inhibitors may target AXL (Tyrosine-protein kinase receptor UFO, also known as AXL oncogene; UniprotKB - P30530). The AXL kinase inhibitors are well-known. For instance, reviews are published disclosing such AXL kinase inhibitors (Myers et aI , J Med Chem. 2016 Apr 28;59(8):3593-608; Grüllich, Recent Results Cancer Res. 2018;211:67-75), the disclosure of which being incorporated herein by reference. Patent applications also disclose AXL kinase inhibitors, for instance and non-exhaustively WO18121228, WO17059280, WO17028797, WO16166250, WO16104617, WO16097918, WO16006706, WO15143692, WO15119122, WO15100117,

WO15068767, WO15017607, WO15012298, WO13115280, WO13074633, WO12135800,

WO12028332, WO10090764, WO10083465, WO10005876, WO10005879, WO09127417,

WO09054864, WO08128072, WO08098139, WO08083353, WO08083357, WO08083354,

WO08083356, WO08083367, WO08080134, WO08045978, WO07030680, the disclosure of which being incorporated herein by reference. Specific examples of AXL kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target c-KIT (Mast/stem cell growth factor receptor Kit, also known as Piebald trait protein (PBT), Proto-oncogene c-Kit, Tyrosine-protein kinase Kit or pl45 c-kit; UniprotKB - P10721). The c-KIT kinase inhibitors are well-known. For instance, reviews are published disclosing such c-KIT kinase inhibitors (Abbaspour Babaei et al, Drug Des Devel Ther. 2016 Aug l;10:2443-59, Zschäbitz et Grüllich; Recent Results Cancer Res. 2018;211:187-198; Miyamoto et aI, Jpn J Clin Oncol. 2018 Jun 1;48(6):503-513; Chen et aI, CurrTop Med Chem. 2017 Nov 20;17(28):3099-3130; Gallogly et Lazarus, J Blood Med. 2016 Apr 19;7:73-83; Pitoia et Jerkovich, Drug Des Devel Ther. 2016 Mar 11;10:1119-31, Chen et Chen, Drug Des Devel Ther. 2015 Feb 9;9:773-9), the disclosure of which being incorporated herein by reference. Patent applications also disclose c-KIT kinase inhibitors, for instance and non-exhaustively

WO19034128, WO18112136, WO18112140, WO17167182, WO17121444, WO14202763,

WO13033116, WO13033203, WO13033167, WO13033070, WO13014170, WO09105712, WO08011080, WO08005877, WO07124369, WO07092403, WO07038669, WO07026251, WO06106437, WO06135719, WO06060381, WO05073225, WO05021531, WO05021537, WO05021544, WO04080462, WO04014903, WO03035049, WO03002114, WO03003006, WO03004006, the disclosure of which being incorporated herein by reference. Specific examples of c-KIT kinase inhibitors are disclosed in the following table. The kinase inhibitors may target Trk (Tropomyosin receptor kinase, also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor, or TRK-transforming tyrosine kinase protein; UniprotKB - P04629 (Trkl), Q16620 (Trk2), Q16288 (TrkB)). The Trk kinase inhibitors are well-known. For instance, reviews are published disclosing such Trk kinase inhibitors (Bhangoo et Sigal, Curr Oncol Rep. 2019 Feb 4;21(2):14, Pacenta et Macy, Drug Des Devel Ther. 2018 Oct 23;12:3549-3561; Cocco et al, Nat Rev Clin Oncol. 2018 Dec;15(12):731- 747; Lange et Lo, Cancers (Basel). 2018 Apr 4;10(4); Rolfo et aI, Expert Opin Investig Drugs. 2015;24(ll):1493-500), the disclosure of which being incorporated herein by reference. Patent applications also disclose Trk kinase inhibitors, for instance and non-exhaustively WO18199166,

WO18079759, WO17135399, WO17087778, WO17006953, WO16164286, WO16161572, WO16116900, WO16036796, WO16021629, WO15200341, WO15175788, WO15143653, WO15148350, WO15148344, WO15143654, WO15148373, WO15148354, WO15143652, WO15089139, WO15039334, WO15042085, WO15039333, WO15017533, WO14129431, WO14105958, WO14078417, WO14078408, WO14078378, WO14078372, WO14078331, WO14078328, WO14078325, WO14078322, WO14078323, WO13183578, WO13176970, WO13161919, WO13088257, WO13088256, WO13009582, WO12158413, WO12137089 WO12116217, WO12034091, WO12037155, WO11006074, WO10048314, WO10033941, WO09054468, WO08135785, WO07123269, WO06135719, WO06123113, WO06087538, WO06087530, WO06082392, WO05049033, WO03027111, the disclosure of which being incorporated herein by reference. Specific examples of Trk kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target ROS1 (Proto-oncogene tyrosine-protein kinase ROS, also known as Proto-oncogene c-Ros, Proto-oncogene c-Ros-1, Receptor tyrosine kinase c-ros oncogene 1 and c-Ros receptor tyrosine kinase; UniprotKB - P08922). The ROS1 kinase inhibitors are well- known. For instance, reviews are published disclosing such ROS1 kinase inhibitors (Lin et Shaw, J Thorac Oncol. 2017 Nov;12(ll):1611-1625; Facchinetti et al, Cancer Treat Rev. 2017 Apr;55:83- 95 ; Rolfo et al, Expert Opin Investig Drugs. 2015;24(ll):1493-500, Yang et Gong, Expert Rev Clin Pharmacol. 2019 Mar;12(3):173-178, Liu et al, Ther Clin Risk Manag. 2018 Jul 20;14:1247-1252; Sgambato et al, Expert Rev Anticancer Ther. 2018 Jan;18(l):71-80), the disclosure of which being incorporated herein by reference. Patent applications also disclose ROS1 kinase inhibitors, for instance and non-exhaustively WO13183578, WO13180183, WO13158859, WO12037155, WO12005299, WO14141129, WO15144801, WO15144799, WO18170381, the disclosure of which being incorporated herein by reference. Specific examples of ROS1 kinase inhibitors are disclosed in the following table.

The kinase inhibitors may target BTK (Tyrosine-protein kinase BTK, also known as Agammaglobulinemia tyrosine kinase (ATK), B-cell progenitor kinase (BPK) and Bruton tyrosine kinase; UniprotKB - Q06187). The BTK kinase inhibitors are well-known. For instance, reviews are published disclosing such BTK kinase inhibitors (Kim HO, Arch Pharm Res. 2019 Feb;42(2):171- 181; Lianget al, Eur J Med Chem. 2018 May 10;151:315-326, Aw et Brown, Drugs Aging. 2017 Jul;34(7):509-527; Wu et al, Oncotarget. 2017 Jan 24;8(4):7201-7207, Wu et al, J Hematol Oncol. 2016 Sep 2;9(1):80), the disclosure of which being incorporated herein by reference. Patent applications also disclose BTK kinase inhibitors, for instance and non-exhaustively WO18002958, WO18001331, WO18009017, WO18035080, WO18088780, WO18090792, WO18095398, WO18133151, WO18145525, A1WO18154131, WO18175512, A1WO18192536, WO18192532, WO18196757, WO18208132, WO18233655, WO19034009, WO17007987, WO17046604, WO17066014, WO17077507, WO17123695, WO17127371, WO17128917, WO17190048, WO17106429,WO16019233, WO16057500, WO16065222, WO16066726, WO16106628,

WO16106626, WO16106629, WO16109215, WO16106627, WO16106623, WO16106624,

WO16106652, WO16112637, WO16161571, WO16161570, WO16196776, WO16196840,

WO16192074, WO16210165, WO16109220, WO15017502, WO15002894, WO15022926,

WO15048689, WO15048662, WO15061247, WO15084998, WO15095102, WO15095099, WO15116485, WO15169233, WO15165279, WO15132799, WO15039612, WO14104757, WO14113932, WO14114185, WO14113942, WO14116504, WO14130693, WO14164558,

WO14151620, WO14152114, WO14161799, WO14187319, WO14210255, WO14005217,

WO14025976, WO14039899, WO14055928, WO14055934, WO14068527, WO14078578,

WO14082598, WO14082598, WO13067264, WO13081016, WO13102059, WO13116382,

WO13148603, WO13152135, WO13185084, WO13067277, WO13067274, WO13059738, WO13010869, WO13010380, WO13010868, WO12170976, WO12135801, WO12021444, WO11153514, WO11152351, WO11029043, WO11029046, WO10126960, WO10056875, WO10009342, WO09156284, WO09098144, WO09053269, WO08121742, WO08039218, WO9954286, the disclosure of which being incorporated herein by reference. Specific examples of BTK kinase inhibitors are disclosed in the following table. The kinase inhibitors may target Syk (Tyrosine-protein kinase SYK, also known as Spleen tyrosine kinase, p72-Syk; UniprotKB - P43405). The Syk kinase inhibitors are well-known. For instance, reviews are published disclosing such Syk kinase inhibitors (Bartaula-Brevik et al, Expert Opin Investig Drugs. 2018 Apr;27(4):377-387; Liu et Mamorska-Dyga, J Hematol Oncol. 2017; 10: 145, Geahlen, Trends Pharmacol Sci. 2014 Aug;35(8):414-22; Norman Expert Opin Ther Pat. 2014 May;24(5):573-95), the disclosure of which being incorporated herein by reference. Patent applications also disclose Syk kinase inhibitors, for instance and non-exhaustively WO19034153,

WO18053189, WO18053190, WO18108083, WO18228475, WO17046302, WO16010809, WO15138273, WO15140051, WO15140054, WO15140055, WO15144614, WO15017610,

WO15061369, WO15094997, WO15095444, WO15095445, WO15100217, WO14051654, WO14048065, WO14060371, WO14064134, WO14074422, WO14086032, WO14093191, WO14100314, WO14176210, WO14176216, WO14023385, WO14027300, WO14031438,

WO14029732, WO14045029, WO13192125, WO13192128, WO13192098, WO13192088,

WO13047813, WO13052391, WO13052394, WO13052393, WO13064445, WO13099041,

WO13104573, WO13104575, WO13109882, WO13124026, WO13126132, WO13124025, WO12002577 WO12025187 WO12025186, WO12061418, WO12123311, WO12123312, WO12130780, WO12151137, WO12154519, WO12154520, WO12154518, WO12167423, WO12167733, WO11086085, WO11014795, WO11014515, WO11075515, WO11075560, WO11079051, WO11092128, WO11112995, WO11117160, WO11134971, WO11144584, WO11144585, WO10068257, WO10068258, WO10097248, WO10147898, WO09131687,

WO09136995, WO09145856, WO09031011, WO08033798, WO07129226, WO07042298,

WO07042299, WO07028445, WO07009681, WO07009681, WO07085540, WO06093247, WO05033316, WO05026158, WO03063794, WO03057695, WO0183485, WO0147922, WO0109134, WO0075113, the disclosure of which being incorporated herein by reference.

Specific examples of Syk kinase inhibitors are disclosed in the following table.

In a very specific aspect, the kinase inhibitor can be selected in the following table 2:

In one aspect, the kinase inhibitor is an inhibitor targeting one or several targets selected in the list consisting of EGFR family, ALK, B-Raf, MEK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, IGF1R, c-Met, JAK family, PDGFR α and β, RET, AXL, c-KIT, TrkA, TrkB, TrkC, ROS1, BTK and Syk. For instance, the kinase inhibitor can be selected from the group consisting of gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS N° 1421373-98-9), poziotinib, WZ4002, Crizotinib, entrectinib, ceritinib, alectinib, lorlatinib, TSR-011, CEP-37440, ensartinib, Vemurafenib, dabrafenib, regorafenib, PLX4720, Cobimetinib, Trametinib, Binimetinib, Selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733, Lenvatinib, Debio-1347, dovitinib, BLU9931, Sorafenib, sunitinib, lestaurtinib, tandutinib, quizartinib, crenolanib, gilteritinib, ponatinib, ibrutinib, Linsitinib, NVP-AEW541, BMS-536924, AG-1024, GSK1838705A, BMS- 754807, PQ 401, ZD3463, NT157, Picropodophyllin (PPP), Tivantinib, JNJ-38877605, PF- 04217903, foretinib (GSK 1363089), Merestinib, Ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, cerdulatinib, gandotinib, momelotinib, pacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, imatinib, pazopanib, Telatinib, bosutinib, nilotinib, cabozantinib,

Bemcentinib, amuvatinib, gilteritinib (ASP2215), glesatinib (MGCD 265), SGI-7079, Larotrectinib, RXDX-102, altiratinib, LOXO-195, sitravatinib, TPX-0005, DS-6051b, fostamatinib, entospletinib and TAK-659.

In a particular aspect, the tyrosine kinase inhibitor is an inhibitor of a protein kinase selected from the group consisting of EGFR, ALK and B-Raf, in particular a protein kinase inhibitor selected from the group consisting of gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS N° 1421373-98-9), poziotinib, WZ4002, Crizotinib, entrectinib, ceritinib, alectinib, lorlatinib, TSR-011, CEP-37440, ensartinib, Vemurafenib, dabrafenib, regorafenib and PLX4720.

In a very specific aspect, the protein kinase inhibitor is a EGFR inhibitor, in particular a EGFR inhibitor selected from the group consisting of gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS N° 1421373-98-9), poziotinib and WZ4002. The treatment with a kinase inhibitor can also be a combination of several kinase inhibitors which target the same kinase or different kinases. Alternatively, a kinase inhibitor may target different kinases. Cancers to be treated

The terms "cancer", "cancerous", or "malignant" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, for example, leukemia, lymphoma, blastoma, carcinoma and sarcoma.

Various cancers are also encompassed by the scope of the invention, including, but not limited to, the following: carcinoma including that of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testis, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma (including cutaneous or peripheral T-cell lymphoma), Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burketts lymphoma; hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia; tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, and schwannomas; tumors of mesenchymal origin including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; other tumors including melanoma, xenoderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer, and teratocarcinoma; melanoma, unresectable stage III or IV malignant melanoma, squamous cell carcinoma, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatocarcinoma, breast cancer, colon carcinoma, and head and neck cancer, retinoblastoma, gastric cancer, germ cell tumor, bone cancer, bone tumors, adult malignant fibrous histiocytoma of bone, childhood malignant fibrous histiocytoma of bone, sarcoma, pediatric sarcoma, myelodysplastic syndromes; neuroblastoma; testicular germ cell tumor, intraocular melanoma, myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases, synovial sarcoma.

In a preferred embodiment of the present invention, the cancer is a solid tumor. For instance, the cancer may be sarcoma and osteosarcoma such as Kaposi sarcome, AIDS-related Kaposi sarcoma, melanoma, in particular uveal melanoma, and cancers of the head and neck, kidney, ovary, pancreas, prostate, thyroid, lung, esophagus, breast in particular triple negative breast cancer (TNBC), bladder, colorectum, liver and biliary tract, uterine, appendix, and cervix, testicular cancer, gastrointestinal cancers and endometrial and peritoneal cancers. Preferably, the cancer may be sarcoma, melanoma, in particular uveal melanoma, and cancers of the head and neck, kidney, ovary, pancreas, prostate, thyroid, lung, esophagus, breast in particular (TNBC), bladder, colorectum, liver, cervix, and endometrial and peritoneal cancers.

In a particular aspect, the cancer can be selected from the group consisting of leukemia, lymphoma, sarcoma, melanoma, and cancers of the head and neck, kidney, ovary, pancreas, prostate, thyroid, lung, esophagus, breast, bladder, brain, colorectum, liver, and cervix.

In another aspect, the cancer can be selected from the group consisting of lung cancer, in particular non-small cell lung cancer, leukemia, in particular acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma, in particular peripheral T-cell lymphoma, chronic myelogenous leukemia, squamous cell carcinoma of the head and neck, advanced melanoma with BRAF mutation, colorectal cancer, gastrointestinal stromal tumor, breast cancer, in particular HER2+ breast cancer, thyroid cancer, in particular advanced medullary thyroid cancer, kidney cancer, in particular renal cell carcinoma, prostate cancer, glioma, pancreatic cancer, in particular pancreatic neuroendocrine cancer, multiple myeloma, and liver cancer, in particular hepatocellular carcinoma.

Regimen, dosages and administration routes

The effective dosage of the DBait nucleic acid molecule and optionally each of the combination partners employed according of the invention may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated. Thus, the dosage regimen is selected in accordance with a variety of factors including the route of administration and the patient status. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites. The DBait nucleic acid molecule can be administered by any suitable administration route including oral, parenteral, intravenous, intratumoral, subcutaneous, intracranial, intra-artery, topical, rectal, transdermal, intradermal, nasal, intramuscular, intra-osseous, and the like.

The Dbait molecule and the optional additional therapeutic agents can have same or different administration regimen. In certain embodiments, a first agent can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), essentially concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent, or any combination thereof. For example, in one embodiment, the first agent can be administered priorto the second therapeutic agent, for e.g. 1 week. In another, the first agent can be administered prior to (for example 1 day prior) and then concomitant with the second therapeutic agent.

The Dbait molecule and the optional additional therapeutic agents may be administered by the same route or by distinct routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Therapeutic agents may also be administered in alternation. The administration route could be oral, parenteral, intravenous, intratumoral, subcutaneous, intracranial, intra-artery, topical, rectal, transdermal, intradermal, nasal, intramuscular, intra-osseous, and the like.

The treatment may include one or several cycles, for instance two to ten cycles, in particular two, three, four or five cycles. The cycles may be continued or separated. For instance, each cycle is separated by a period of time of one to eight weeks, preferably three to four weeks.

Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting. EXAMPLES Example 1

Synthesis of the nucleic acid molecules

Materials and Methods Dbait32Hc molecules synthesis

Dbait32Hc molecules used as control molecule were obtained by automated solid phase oligonucleotide synthesis from Eurogentec (Seraing, Belgium).

Briefly, the synthesis of Dbait32Hc molecule as shown in Figure 1 required several separate steps of synthesis of strands, and further processes to reach double stranded molecule. Independent synthesis, purification and ultrafiltration steps were achieved for synthesize the first strand (strand A), and the complementary (strand B). Then a conjugation process to gather both strands was performed, followed by purification and ultrafiltration step, and then lyophilization step.

Reduction of the number of steps in the synthesis_of new nucleic acid molecules - Example with OX409 The synthesis of OX409 from Axolabs (Germany) was based on standard solid-phase DNA synthesis using phosphoramidite chemistry (dA(Bz); dC(Ac); dG(IBu); dT (-)), HEG and Chol6 phosphoramidites.

Detritylation steps were performed with 3% DCA in toluene (v/v), oxidations were performed with 50 mM iodine in pyridine/water 9/1 and sulfurizations were performed with 50 mM DDTT in pyridine/ACN 1/1. The capping was done with 20% NMI in ACN, together with 20% Ac20 in 30% 2,6-lutidine/ACN (40/60). The cleavage and deprotection are performed with AMA, a mixture of aq ammoniac (30%)/aq methylamine (40%) (1/1) for 3 hours at 45°C.

The crude solution was loaded onto a preparative RP-HPLC column (Waters Xbridge C18)). Purification was then performed eluting with a salt gradient from 100% of TEAA (100 mM) to 50/50 TEAA (100mM)/ACN 95% in TEAA (lOOmM). The pooled RP- fractions were incubated at pH 4.5 and 37°C to remove the DMT group and a second purification was performed by AEX-HPLC with a gradient from 100% NaOH (10 mM) to 100% NaBr (1.4M). The pooled fractions were neutralized and desalted using Sephadex G25.

Purity of OX409™: 86.2% by AEX-HPLC; Molecular weight by ESI-MS: 20471.7 Da. The synthesis of OX409 required few steps of synthesis as shown in Figure 1: double stranded molecule was synthesized in single step, completed by purifications, ultrafiltration, and then lyophilization steps.

Example 2 OX409 lures and activates DNA-PK

Materials and Methods

Activity of OX409

DNA-PK ATPase activity is induced by double-stranded oligonucleotides. The activity of OX409 was measured by measuring the ATPase activity of DNA-PK. Dbait32Hc molecules obtained by automated solid phase oligonucleotide synthesis were used as control.

DNA-PK activity assay

DNA-PK ATPase activity was monitored using an internal developed assay measuring the kinetics of ATP hydrolysis by DNA-PK enzymes (principle of the assay as shown in Figure 2). The assay is an adaptation of the reference SignaTECT DNA-PK Assay (Promega) that measures the phosphorylation of a P53 substrate peptide (specific DNA-PK substrate) using ³²P ATP. Experimental conditions have been adapted to monitor DNA-PK kinase activity from the rate of ATP hydrolysis during the kinase reaction. Briefly, DNA-PK enzyme (160U; Promega, V5811), peptide substrate (140μg; eurogentec), pyruvate kinase (4.5U; sigma Aldrich, P0294), NADH (200μg/ml; Sigma Aldrich), ATP (0.2mM; Sigma Aldrich) and increasing concentrations of control compound Dbait32Hc and of OX409 molecule were incubated for 90 minutes at 33°C. The decrease of the amount of NADH is correlated to the amount of ATP hydrolyzed by DNA-PK. Kinetic of ATP hydrolysis (pmol/min/U DNA-PK) was measured using a spectrophotometer (BMG; absorbance at 340nm every minute) and calculated using the following formula:

DNA-PK ATPase activity (pmol/min/U) = ((slope [abs.min^-1]/(ε[L.mol^-1.cm ^-1 ] x optical distance [cm])) x reaction volume [L] x 10¹²)/160 ε of NADH = 6220 L mol ^-1cm ^-1 Optical distance = 0.4cm Reaction volume = 70μL

Vmax and Km was calculated using GraphPadPrim software (GraphPad, San Diego, USA). Results

It was analyzed if OX409 could be detected by DNA-PK enzyme as a double-strand DNA break (DSB), since binding of Ku proteins followed by DNA-PKcs recruitment and activation of its kinase activity are the earliest events in DSB repair by NHEJ pathway. The activation of DNA-PK by OX409 compared to Dbait32Hc was monitored using the DNA-PK activity assay. OX409 induced a higher ATP hydrolysis rate with a Vmaxof 0.12 pmol/min/unit of DNA-PK compared to Dbait32Hc (Vmax = 0.11 pmol/min/unit of DNA-PK). Moreover, the Km value of OX409 (0.109 nM) was lower than Dbait32Hc (0.199nM), indicating a higher affinity of DNA-PK to OX409 compared to Dbait32Hc (Figure 3).

Example 3 OX409 recruits and activates DNA-PK and PARP proteins

Materials and Methods

Cell culture, molecules and transfection Cell cultures were performed with the triple negative breast cancer cell line MDA-MB-231. Cells were grown in complete L15 Leibovitz medium and maintained at 37°C in a humidified atmosphere at 0% CO2.

Dbait32Hc molecules were obtained by automated solid phase oligonucleotide synthesis from Eurogentec (Seraing, Belgium), and OX409 from Axolabs (Germany). Transfection of molecules into cells was performed with JetPRIME reagent (Polyplus, lllkirch, France) in a ratio of 2mI JetPRIME per μg of DNA in 2ml medium (in 60mm diameter culture plates) for 24 hours according to the manufacturer's instructions. Briefly, 1.10⁶ MDA-MB-231 cells were seeded in 60mm diameter plates and incubated at 37°C during 24hours. 2μg of Dbait32Hc or OX409 were incubated with 4mI of JetPRIME reagent in 200mI of JetPRIME bufferfor 10 minutes. The transfection mix was then added to the cells in 2ml of complete medium and incubated during 24 hours.

Western blot analysis

Cells treated for 24 hours with Dbait32Hc or OX409 were harvested and lysed in RIPA buffer (150 mM NaCI, 50 mM Tris-base, 5 mM EDTA, 1 % NP-40,0.25 % deoxycholate, pH 7.4) with protease and phosphatase inhibitors (Roche Applied Science, Germany). Protein concentrations were measured using the BCA protein assay (Thermo Fisher Scientific, USA). Equal amounts (15 μg) of the protein were electrophoresed using SDS-PAGE (12% gel), transferred to nitrocellulose membranes, blocked with 5 % skim milk in TBS Tween 1 % for 1 hour at room temperature and then incubated with primary antibodies overnight at 4°C. Following washes with TBS/Tween 1%, membranes were incubated with the secondary antibody for 1 hour at room temperature. The bound antibodies were detected using the Enhanced Chemiluminescence western blotting substrate kit (Ozyme, USA). Western blotting was done with the following antibodies: anti-Pan- ADP Ribose binding reagent (dilution 1/1,500; Millipore MABE1016), primary monoclonal mouse anti-βactin (dilution 1/10,000, Sigma A1978), secondary goat anti-rabbit IgG, HRP conjugate (dilution 1/2,000, Millipore 12-348) and secondary goat anti-mouse IgG, HRP conjugate (dilution 1/2,000, Millipore 12-348).

Result

DNA-PK and PARP proteins bind to DSBs with a high affinity. Upon binding, DNA-PK activates its down-stream targets such as histone H2AX, and PARP proteins are auto"PARylated" and activate other target proteins by the addition of polymers of poly(ADP-Ribose) (PAR) referred to as PARylation (Figure 4). DNA-PK and PARP activation in cells was measured by monitoring the ability of Dbait32Hc and OX409 to recruit DNA-PK and induce the phosphorylation of histone H2AX (γH2AX), as well as their ability to recruit PARP and induce the synthesis of PAR chains. Analysis of γH2AX and PAR-modified proteins in MDA-MB-231 cells transfected with Dbait32Hc or OX409 revealed an efficient activation of DNA-PK and PARP by both molecules (Figure 4). Thus, compared to Dbait32Hc, OX409 retained the ability of recruiting and activating these enzymes.

Claims

1- A DBait nucleic acid molecule comprising a double-stranded nucleic acid moiety, the 5'end of the first strand and the 3'end of the complementary strand being linked together by a loop; the double-stranded nucleic acid moiety having the following sequence

the loop being

-O-P(X)OH-O-{[(CH₂)₂-O]_g-P(X)OH-O}_rK-O-P(X)OH-O-{[(CH₂)₂-O]_h-P(X)OH-O-}_s (l) with r and s being independently an integer 0 or 1; g and h being independently an integer from 1 to 7 and the sum g + h being from 4 to 7; X being O or S; with K being

2- The Dbait nucleic acid molecule according to claim 1, wherein the double-stranded nucleic acid moiety has the following sequence

wherein internucleotide linkages "s" refer to phosphorothioate internucleotide linkages. 3- The Dbait nucleic acid molecule according to claim 1 or 2, wherein r is 1, s is 0 and g is an integer from 5 to 7, preferably 6.

4- The Dbait nucleic acid molecule according to any one of claims 1 to 3, wherein i and j are 1 and k and I are both 1 or 2.

5- The Dbait nucleic acid molecule according to any one of claims 1 to 3, wherein m is an integer between 4 and 6, preferably 5. 6- The Dbait nucleic acid molecule according to anyone of claims 1 to 5, wherein the DBait nucleic acid molecule is

7- A pharmaceutical or veterinary composition comprising a Dbait nucleic acid molecule according to any one of claims 1 to 6.

8- The pharmaceutical or veterinary composition according to claim 7, further comprising a therapeutic agent, in particular selected from a chemotherapeutic agent such as a DNA damaging antitumoral agent, a PARP inhibitor, a kinase inhibitor, a HDAC inhibitor, an immunotherapeutic agent, a hormonal therapeutic agent or any combination thereof.

9- A Dbait nucleic acid molecule according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 or 8 for use as a drug.

10- A Dbait nucleic acid molecule according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 or 8 for use for treating a cancer. 11- The Dbait nucleic acid molecule or pharmaceutical composition for use according to claim 9 or 10, wherein it is used in combination with radiotherapy, a chemotherapeutic agent such as a DNA damaging antitumoral agent, a PARP inhibitor, a kinase inhibitor, a HDAC inhibitor, a KRAS inhibitor, an immunotherapeutic agent, a hormonal therapeutic agent or any combination thereof.

12- The Dbait nucleic acid molecule or pharmaceutical composition for use according to any one of claims 9 to 11, wherein the cancer is selected from leukemia, lymphoma, sarcoma, melanoma, and cancers of the head and neck, kidney, ovary, pancreas, prostate, thyroid, lung, esophagus, breast, bladder, brain, colorectum, liver, and cervix.

13-The composition according to claim 8 or the Dbait nucleic acid molecule or pharmaceutical composition for use according to any one of claims 9 to 12, wherein the chemotherapeutic agent is selected from the group consisting of a platinum agent such as cisplatin, oxaliplatin and carboplatin, an alkylating agent, a camptothecin, a nitrogen mustard, an antibiotic, an antimetabolite, and a vinca alkaloid.

14- The composition according to claim 8 or the Dbait nucleic acid molecule or pharmaceutical composition for use according to any one of claims 9 to 12, wherein the PARP inhibitor is selected from the group consisting of rucaparib (AG014699, PF-01367338), olaparib (AZD2281), veliparib (ABT888), iniparib (BSI 201), niraparib (MK 4827), talazoparib (BMN673), AZD 2461, CEP 9722, E7016, INO-1001, LT-673, MP-124, NMS-P118, XAV939, analogs, derivatives or a mixture thereof.

15- The composition according to claim 8 or the Dbait nucleic acid molecule or pharmaceutical composition for use according to any one of claims 9 to 12, wherein the kinase inhibitor is selected from the group consisting of an inhibitor targeting one or several targets selected in the list consisting of EGFR family, ALK, B-Raf, MEK, FGFR1, FGFR2, FGFR3, FGFR4, FLT3, IGF1R, c-Met, JAK family, PDGFR α and β, RET, AXL, c-KIT, TrkA, TrkB, TrkC, ROS1, BTK and Syk, more preferably selected from the group consisting of gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS N° 1421373-98-9), poziotinib, WZ4002, Crizotinib, entrectinib, ceritinib, alectinib, lorlatinib, TSR-011, CEP-37440, ensartinib, Vemurafenib, dabrafenib, regorafenib, PLX4720, Cobimetinib, Trametinib, Binimetinib, Selumetinib, PD- 325901, CI-1040, PD035901, U0126, TAK-733, Lenvatinib, Debio-1347, dovitinib, BLU9931, Sorafenib, sunitinib, lestaurtinib, tandutinib, quizartinib, crenolanib, gilteritinib, ponatinib, ibrutinib, Linsitinib, NVP-AEW541, BMS-536924, AG-1024, GSK1838705A, BMS-754807, PQ 401, ZD3463, NT157, Picropodophyllin (PPP), Tivantinib, JNJ-38877605, PF-04217903, foretinib (GSK 1363089), Merestinib, Ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, cerdulatinib, gandotinib, momelotinib, pacritinib, PF-04965842, upadacitinib, peficitinib, fedratinib, imatinib, pazopanib, Telatinib, bosutinib, nilotinib, cabozantinib, Bemcentinib, amuvatinib, gilteritinib (ASP2215), glesatinib (MGCD 265), SGI-7079, Larotrectinib, RXDX-102, altiratinib, LOXO-195, sitravatinib, TPX-0005, DS-6051b, fostamatinib, entospletinib and TAK-659. 16- The composition according to claim 8 or the Dbait nucleic acid molecule or pharmaceutical composition for use according to any one of claims 9 to 12, wherein the KRAS inhibitor is selected from the group consisting of specific covalent KRAS inhibitors and multivalent small-molecule pan KRAS inhibitors, more preferably selected from the group consisting of AMG 510 (Amgen/Carmot Therapeutics), MRTX-849 (Mirati Therapeutics), ARS-3248 / JNJ-74699157 (Johnson & Johnson/ Wellspring Biosciences), Compound B (Sanofi/X-Chem Pharmaceuticals), LY3499446 (Eli Lilly), ARS-853, ARS-1620, BI-2852, BI-1701963 (Boehringer Ingelheim), mRNA- 5671 (Moderna Therapeutics), G12D inhibitor (Mirati), RAS(On)inhibitors (Revolution medicines) and BBP-454 (BridgeBio Pharma).