Biomarkers for predicting the sensitivity and response of protein kinase CK2-mediated diseases to CK2 Inhibitors
Disclosed are biomarkers for determining the sensitivity of protein kinase CK2-mediated diseases, such as proliferative and/or inflammatory disorders, to treatment with CK2 inhibitors. These biomarkers can be used to predict or select subjects likely to be responsive to treatment with a CK2 inhibitor, and to treat or monitor subjects undergoing treatment with a CK2 inhibitor.
1 . A method for monitoring the response of a subject being treated with a CK2 inhibitor, said method comprising:
(a) determining the level of a biomarker in a biological sample derived from the subject at a time point .during or after administration of the CK2 inhibitor, wherein the biomarker is selected from the level of phosphorylated Akt S129, the ratio of phosphorylated Akt S 129 to total Akt, the level of phosphorylated Akt S473, the ratio of phosphorylated Akt S 473 to total Akt, the level of phosphorylated p21 T145, the ratio of phosphorylated p21 T 145 to total p21, the level of phosphorylated NF-κB S529, the ratio of phosphorylated NF-κB S529 to total NF-κB, the level of phosphorylated STAT3 T705, the ratio of phosphorylated STAT3 T705 to total STAT3, the level of phosphorylated JAK2 Y1007/1008, and the ratio of phosphorylated JAK2 Y1007/1008 to total JAK2; and
(b) comparing the level of the biomarker in the biological sample with a reference level of the biomarker;
wherein a decrease in the level of the biomarker in the biological sample compared to the reference level of the biomarker is indicative of a positive response to treatment with said CK2 inhibitor.
2 . The method of claim 1 , wherein the reference level of the biomarker is selected from the group consisting of (1) the level of said biomarker from the subject prior to administration of the CK2 inhibitor; (2) the level of said biomarker from a reference population; (3) a pre-assigned level for said biomarker; and (4) the level of said biomarker from the subject at a second time point prior to the first time point.
3 . The method of claim 1 , wherein said biological sample is selected from a cell, a tissue, a tissue culture, a tumor, or a biological fluid derived from said subject.
4 . The method of claim 3 , wherein said biological fluid is selected from plasma, serum, or PBMCs.
5 . The method of claim 3 , wherein said cell is a circulating tumor cell (CTC).
6 . The method of claim 1 , wherein said subject suffers from a cancer or malignancy.
7 . The method of claim 6 , wherein said cancer or malignancy is selected from breast cancer, inflammatory breast cancer (IBC), pancreatic cancer, prostate cancer, lung cancer, colon cancer, melanoma, and multiple myeloma.
8 . The method of claim 1 , wherein said subject suffers from a CK-2 mediated autoimmune, inflammatory, or infectious disorder.
9 . The method of claim 1 , wherein said CK2 inhibitor is CX-4945.
10 . A method for monitoring the response of a subject being treated with a CK2 inhibitor, said method comprising:
(a) determining the level of mRNA and/or protein expression of a biomarker in a biological sample derived from the subject at a time point during or after administration of the CK2 inhibitor, wherein the biomarker is selected from IL-6, IL-8, CK2α, CK2α′, CK2β, VEGF, and HIF-1α; and
(b) comparing the level of the biomarker in the biological sample with a reference level of the biomarker;
wherein a decrease in the level of the biomarker in the biological sample compared to the reference level of the biomarker is indicative of a positive response to treatment with said CK2 inhibitor.
11 . The method of claim 10 , wherein the reference level of the biomarker is selected from the group consisting of (1) the level of said biomarker from the subject prior to administration of the CK2 inhibitor; (2) the level of said biomarker from a reference population; (3) a pre-assigned level for said biomarker; and (4) the level of said biomarker from the subject at a second time point prior to the first time point.
12 . The method of claim 10 , wherein said biological sample is selected from a cell, a tissue, a tissue culture, a tumor, or a biological fluid derived from said subject.
13 . The method of claim 12 , wherein said biological fluid is selected from plasma, serum, or PBMCs.
14 . The method of claim 12 , wherein said cell is a circulating tumor cell (CTC).
15 . The method of claim 10 , wherein said subject suffers from a cancer or malignancy.
16 . The method of claim 15 , wherein said cancer or malignancy is selected from breast cancer, inflammatory breast cancer (IBC), pancreatic cancer, prostate cancer, lung cancer, colon cancer, melanoma, and multiple myeloma.
17 . The method of claim 10 , wherein said subject suffers from a CK-2 mediated autoimmune, inflammatory, or infectious disorder.
18 . The method of claim 10 , wherein said CK2 inhibitor is CX-4945.
19 . A method for predicting the clinical response of a CK2-mediated disease to treatment with a CK2 inhibitor in a subject, said method comprising determining the level of one or more biomarkers in a biological sample derived from the subject, wherein an elevated level of said one or more biomarkers relative to a control biological sample is indicative of sensitivity of the CK2-mediated disease to treatment with said CK2 inhibitor, and wherein said biomarker is selected from the level of phosphorylated Akt S129, the ratio of phosphorylated Akt S 129 to total Akt, the level of phosphorylated Akt S473, the ratio of phosphorylated Akt S 473 to total Akt, the level of phosphorylated p21 T145, the ratio of phosphorylated p21 T145 to total p21, the level of phosphorylated NF-κB S529, the ratio of phosphorylated NF-κB S529 to total NF-κB, the level of phosphorylated STAT3 T705, the ratio of phosphorylated STAT3 T705 to total STAT3, the level of phosphorylated JAK2 Y1007/1008, the ratio of phosphorylated JAK2 Y1007/1008 to total JAK2, the expression level of IL-6, the expression level of IL-8, the expression level of CK2α, the expression level of CK2α′, the expression level of CK2β, the expression level of VEGF, and the expression level of HIF-1α.
20 . The method of claim 19 , wherein said biological sample is selected from a cell, a tissue, a tissue culture, a tumor, or a biological fluid derived from said subject.
21 . The method of claim 20 , wherein said biological fluid is selected from plasma, serum, or PBMCs.
22 . The method of claim 20 , wherein said cell is a circulating tumor cell (CTC).
23 . The method of claim 19 , wherein said subject suffers from a cancer or malignancy.
24 . The method of claim 23 , wherein said cancer or malignancy is selected from breast cancer, inflammatory breast cancer (IBC), pancreatic cancer, prostate cancer, lung cancer, colon cancer, melanoma, and multiple myeloma.
25 . The method of claim 19 , wherein said subject suffers from a CK-2 mediated autoimmune, inflammatory, or infectious disorder.
26 . The method of claim 19 , wherein said CK2 inhibitor is CX-4945.
27 . A method for predicting the clinical response of a cancer or malignancy to treatment with a CK2 inhibitor in a subject, said method comprising:
(a) determining the level of CK2α′ mRNA and/or protein expression in a biological sample derived from the subject; and
(b) determining the level of p-Akt S129 and/or the ratio of p-Akt S129 to total Akt in a biological sample derived from the subject;
wherein a positive correlation between the level of CK2α′ mRNA and/or protein expression and the level of p-Akt S129 and/or ratio of p-Akt S129 to total Akt is indicative of sensitivity of the cancer or malignancy to treatment with said. CK2 inhibitor.
28 . The method of claim 27 , wherein said biological sample is selected from a cell, a tissue, a tissue culture, a tumor, or a biological fluid derived from said subject.
29 . The method of claim 28 , wherein said biological fluid is selected from plasma, serum, or PBMCs.
30 . The method of claim 27 , said cancer or malignancy is breast cancer, inflammatory breast cancer (IBC), or multiple myeloma.
31 . The method of claim 27 , wherein said CK2 inhibitor is CX-4945.