A NEUROPILIN ANTAGONIST IN COMBINATION WITH A P38ALPHA-KINASE INHIBITOR FOR THE TREATMENT OF CANCER
Neuropilin-1 is henceforth a relevant target in cancer treatment, however way-of-action is remains partly elusive and the development of small inhibitory molecules is therefore required for its study. Here, the inventors report that two neuropilin small-sized antagonists (NRPa-47, NRPa-48), VEGF-A165/NRP-1 binding inhibitors, are able to decrease VEGF-Rs phosphorylation and to modulate their downstream cascades in triple negative breast cancer cell line (MDA-MB-231). In particular, the inventors showed for the first time, how NRPa may altered tumor cell signaling and contributed in the down-modulation of the cancer therapeutic key factor p38α-kinase phosphorylation. More importantly, the association of NRPa with a p38α inhibitor leads to additional and/or synergistic effect of these drugs (depending of the dose used) for significantly reducing breast cancer cell proliferation Thus, the efficient association of NRPa and p38α-kinase inhibitors are thus credible for the treatment of cancer.
1 . A method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective combination comprising at least one neuropilin antagonist and at least one p38α-kinase inhibitor.
2 . The method of claim 1 wherein the subject is a human.
3 . The method of claim 1 wherein the subject is a non-human mammal.
4 . The method of claim 1 wherein the cancer is a hematopoietic or a non-hematopoietic cancer.
5 . The method of claim 1 wherein the cancer is breast cancer.
6 . The method of claim 1 wherein the cancer is triple-negative breast cancer.
7 . The method of claim 1 wherein the cancer is neuropilin positive.
8 . The method of claim 1 wherein the at least one neuropilin antagonist is selected from the group consisting of antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, neuropilin-specific aptamers, anti-neuropilin antibodies, neuropilin-binding fragments of anti-neuropilin antibodies, neuropilin-binding small molecules, neuropilin-binding peptides, and polypeptides that specifically bind neuropilin, such that the interaction between the neuropilin antagonist and neuropilin results in a reduction or cessation of neuropilin activity or expression.
9 . The method of claim 1 wherein the at least one neuropilin antagonist inhibits the interaction between a neuropilin protein and a binding partner of the neuropilin protein.
10 . The method of claim 1 wherein the at least one neuropilin antagonist is an antibody that specifically binds to a neuropilin and neutralizes its activity to activate neuropilin signalling pathway.
11 . The method of claim 1 wherein the at least one neuropilin antagonist is NRPa-47 or NRPa-48.
12 . The method of claim 1 wherein the at least one p38α-kinase inhibitor is selected from the group consisting of antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, p38-α-specific aptamers, anti-p38α antibodies, p38α-binding fragments of anti-p38α antibodies, p38α-binding small molecules, p38α-binding peptides, and polypeptides that specifically bind p38α, such that the interaction between the at least one p38α-kinase inhibitor and p38α results in a reduction or cessation of p38α kinase activity or expression.
13 . The method of claim 1 wherein the at least one p38α-kinase inhibitor is selected from the group consisting of ARRY-371797, ARRY-614, AZD-7624, ralimetinib, LY-3007113, FX005, GSK610677, GW856553, SB-681323, KC706, UR-13870, PF-03715455, VX-745, SCID-469, PH-797804, VX-702, SB-202190, SB-203580, SB-239063, BIRB-796, BMS-582949, and pamapimod.
14 . The method of claim 1 wherein the at least one neuropilin antagonist is NRPa-47 and the at least one p38α-kinase inhibitor is Ralimetinib.
15 . The method of claim 1 wherein the at least one neuropilin antagonist is NRPa-48 and the at least one p38α-kinase inhibitor is Ralimetinib.
16 . The method of claim 9 wherein the neuropilin protein is NRP-1.
17 . The method of claim 16 , wherein the binding partner of the neuropilin protein is VEGF-A 165 .
18 . The method of claim 10 wherein the neuropilin protein is NRP-1 or NRP-2).
19 . The method of claim 18 , wherein the at least one neuropilin antagonist inhibits the binding of the neuropilin protein and VEGF-A 165 .