Methods for the treatment of a cancer or fibrotic disorder associated with MENA or MENA(INV) by administering a map kinase inhibitor
Phosphorylation and dephosphorylation of MENA and MENA isoforms regulates the metastatic activity of cancer cells. Administration of a MENA kinase inhibitor results in significant reduction in the development of cancer metastasis in established and developing tumors. Administration of a MENA kinase inhibitor in conjunction with a tyrosine kinase inhibitor enhances efficacy of tyrosine kinase inhibitor therapy. Administration of a MENA kinase inhibitor in conjunction with anti-microtubule agent results in significant reduction in chemotherapy-induced tumor cell dissemination and enhances efficacy of anti-microtubule therapy.
1. A method for the treatment of a cancer or fibrotic disorder associated with elevated MENA protein (SEQ ID NO: 1) and/or MENA INV protein (SEQ ID NO: 3) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a protein kinase inhibitor that inhibits phosphorylation of a serine residue on a MENA isoform substrate, selected from at least one of MENA protein (SEQ ID NO: 1) or MENA INV protein (SEQ ID NO: 3), wherein the protein kinase inhibitor inhibits the transfer of phosphate to Ser125 of SEQ ID NO:1 and/or inhibits the transfer of phosphate to Ser144 of SEQ ID NO:3 and wherein the protein kinase inhibitor inhibits a MAP kinase signaling pathway.
2. The method according to claim 1 , wherein the protein kinase inhibitor is at least one of a MAPKAPK2/MK2 inhibitor, p38 MAPK inhibitor, and MEK inhibitor.
3. The method according to claim 2 , wherein the protein kinase inhibitor is a MAPKAPK2/MK2 inhibitor.
4. The method according to claim 1 , wherein the protein kinase inhibitor is administered to the subject orally, intravenously, intramuscularly, intraperitoneally, intrapulmonarily, intratumorally, intranasally, intrathecally or subcutaneously.
5. The method according to claim 1 , wherein the protein kinase inhibitor is co-administered to the subject with another therapeutic agent.
6. The method according to claim 5 , wherein the protein kinase inhibitor is co-administered to the subject with a tyrosine kinase inhibitor or an anti-microtubule agent.
7. The method according to claim 6 , wherein the protein kinase inhibitor is administered to the subject prior to, in conjunction with, or subsequent to administration of the tyrosine kinase inhibitor or anti-microtubule agent.
8. The method according to claim 7 , wherein the protein kinase inhibitor is co-administered to the subject with an anti-microtubule agent selected from docetaxel, paclitaxel, albumin-bound paclitaxel, and cabazitaxel.
9. The method according to claim 6 , wherein the protein kinase inhibitor is co-administered to the subject with a tyrosine kinase inhibitor specific to the group of tyrosine kinase receptors selected from the group consisting of EGF receptor (EGFR), HER2/neu, c-SRC, hepatocyte growth factor receptor (HGFR), insulin-like growth factor 1 receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and VEGF receptor; or gefitinib.
10. The method according to claim 1 , wherein the disorder is cancer.
11. The method according to claim 10 , wherein the cancer is selected from multiple myeloma, acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, promyelocytic leukemia, B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkiti's lymphoma, mast cell tumors, Hodgkin's disease, non-Hodgkin's disease, myelodysplasia syndrome, fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma, schwannomas, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenodenna pigmentosum, keratoctanthoma, thyroid follicular cancer, Kaposi's sarcoma, melanoma, teratotna, rhabdomyosarcoma, metastatic and bone disorders, cancer of the bone, mouth/pharynx, esophagus, larynx, stomach, intestine, colon, rectum, lung, liver, pancreas, nerve, brain, head and neck, throat, ovary, uterus, prostate, testis, bladder, kidney, breast, gall bladder, cervix, thyroid, prostate, and skin, non-small cell lung cancer, small cell lung cancer, glioma, and glioblastoma multiforme.
12. The method according to claim 10 , wherein the cancer is a metastatic cancer.
13. The method according to claim 12 , wherein the cancer is a lung metastasis.